IP Library › Granted Patent US 12,577,255
Granted Patent B2
US 12,577,255 · App. 17/570,197 · Granted Mar 17, 2026

MDM2-based modulators of proteolysis and associated methods of use

Inventors: Andrew P. Crew (Chester, CT); Craig M. Crews (New Haven, CT); Hanqing Dong (Madison, CT); Yimin Qian (Plainsboro, NJ); Jing Wang (Milford, CT)
Assignee: Arvinas Operations, Inc.
C07D495/14A61K31/337A61K31/4184A61K31/436A61K31/4545A61K31/4995A61K31/506A61K31/593A61K31/664A61K31/704A61K45/06A61K47/55C07D207/16C07D401/12C07D401/14C07D405/14C07D417/12
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Quick Facts
Patent No.
US 12,577,255
App. No.
17/570,197
Granted
Mar 17, 2026
Kind
B2
Abstract

The description relates to MDM2 binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the MDM2 E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

Claims (5)

1 . A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

2 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, additive, and/or excipient.

3 . The pharmaceutical composition of 2 , further comprising an additional bioactive agent, wherein the additional bioactive agent is an anticancer agent.

4 . The composition according to 2 , wherein said anticancer agent is selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, dasatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 1 KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl -quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser (t-Bu) 6 , Azgly 10 ](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(t-Bu)-Leu-Arg-Pro-Azgly-NH 2 acetate [C 59 H 84 N 18 O 4 —(C 2 H 4 O 2 ) X where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevac, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 11, 2022
From: CREW, ANDREW P.; CREWS, CRAIG M.; DONG, HANQING; QIAN, YIMIN; WANG, JING
To: ARVINAS, INC.
Reel/Frame 058618/0354 →
CHANGE OF NAME Recorded Jan 11, 2022
From: ARVINAS, INC.
To: ARVINAS OPERATIONS, INC.
Reel/Frame 058700/0875 →
Continuity (3)
Continuation 15206497 · Jul 11, 2016
Provisional Application 62191193 · Jul 10, 2015
Related Publication 20220127279A1 · Apr 28, 2022
References Cited (224)
US 6306663B1 · Kenten et al. · 2001 [cited by applicant]
US 6670348B1 · Rosen et al. · 2003 [cited by applicant]
US 7041298B2 · Deshaies et al. · 2006 [cited by applicant]
US 7208157B2 · Sakamoto et al. · 2007 [cited by applicant]
US 7915293B2 · Ramesh · 2011 [cited by applicant]
US 9500653B2 · Crews et al. · 2016 [cited by applicant]
US 9632089B2 · Crews et al. · 2017 [cited by applicant]
US 20080214501A1 · Zhengying et al. · 2008 [cited by applicant]
US 20100286127A1 · Miyoshi · 2010 [cited by applicant]
US 20120270800A1 · Verdine et al. · 2012 [cited by applicant]
US 20140088143A1 · Jain · 2014 [cited by applicant]
US 20140235629A1 · Bartberger et al. · 2014 [cited by applicant]
US 20140243372A1 · Rew · 2014 [cited by applicant]
US 20140256700A1 · Poss · 2014 [cited by applicant]
US 20140302523A1 · Crews et al. · 2014 [cited by applicant]
US 20140356322A1 · Crews et al. · 2014 [cited by applicant]
US 20140371206A1 · Albrecht et al. · 2014 [cited by applicant]
US 20150119435A1 · Crews et al. · 2015 [cited by applicant]
US 20150141470A1 · Garraway et al. · 2015 [cited by applicant]
US 20150148342A1 · Combs et al. · 2015 [cited by applicant]
US 20150225381A1 · Lu · 2015 [cited by applicant]
US 20150259288A1 · Nam et al. · 2015 [cited by applicant]
US 20150291562A1 · Crew et al. · 2015 [cited by applicant]
US 20150344473A1 · Du et al. · 2015 [cited by applicant]
US 20160022642A1 · Crews et al. · 2016 [cited by applicant]
US 20160045607A1 · Crew et al. · 2016 [cited by applicant]
US 20160058872A1 · Crew et al. · 2016 [cited by applicant]
US 20160136230A1 · Campos et al. · 2016 [cited by applicant]
US 20160176864A1 · Norris et al. · 2016 [cited by applicant]
US 20160214972A1 · Jin et al. · 2016 [cited by applicant]
US 20160272639A1 · Crew et al. · 2016 [cited by applicant]
US 20160368911A1 · Campos et al. · 2016 [cited by applicant]
US 20170008904A1 · Crew et al. · 2017 [cited by applicant]
US 20170037004A1 · Crew et al. · 2017 [cited by applicant]
US 20170065719A1 · Qian et al. · 2017 [cited by applicant]
US 20170121321A1 · Crews et al. · 2017 [cited by applicant]
US 20170281784A1 · Wang et al. · 2017 [cited by applicant]
US 20170307614A1 · Crews et al. · 2017 [cited by applicant]
US 20170327469A1 · Crew et al. · 2017 [cited by applicant]
US 20180015087A1 · Liu et al. · 2018 [cited by applicant]
US 20180072711A1 · Crew et al. · 2018 [cited by applicant]
US 20180099940A1 · Crew et al. · 2018 [cited by applicant]
US 20180125821A1 · Crew et al. · 2018 [cited by applicant]
US 20180147202A1 · Crew et al. · 2018 [cited by applicant]
US 20180155322A1 · Crew et al. · 2018 [cited by applicant]
US 20180177750A1 · Crew et al. · 2018 [cited by applicant]
US 20180179183A1 · Crew et al. · 2018 [cited by applicant]
US 20180193470A1 · Crew et al. · 2018 [cited by applicant]
US 20180215731A1 · Crew et al. · 2018 [cited by applicant]
US 20180228907A1 · Crew et al. · 2018 [cited by applicant]
US 20180237418A1 · Crew et al. · 2018 [cited by applicant]
US 20180256586A1 · Crew et al. · 2018 [cited by applicant]
EP 2985285 · 2016 [cited by applicant]
JP 2009517439 · 2009 [cited by applicant]
WO WO2002066512 · 2002 [cited by applicant]
WO WO2006113942 · 2006 [cited by applicant]
WO WO2007115289 · 2007 [cited by applicant]
WO WO2010107485 · 2010 [cited by applicant]
WO WO2011008260A2 · 2011 [cited by applicant]
WO WO2011143660 · 2011 [cited by applicant]
WO WO2011143669A2 · 2011 [cited by applicant]
WO WO2012003281 · 2012 [cited by applicant]
WO WO2012007409 · 2012 [cited by applicant]
WO WO2012040389 · 2012 [cited by applicant]
WO WO2012040527 · 2012 [cited by applicant]
WO WO2012078559 · 2012 [cited by applicant]
WO WO2012090104 · 2012 [cited by applicant]
WO WO2013106643 · 2013 [cited by applicant]
WO WO2013106646 · 2013 [cited by applicant]
WO WO2013170147 · 2013 [cited by applicant]
WO WO2013175417 · 2013 [cited by applicant]
WO WO2013178570A1 · 2013 [cited by applicant]
WO WO2014001356 · 2014 [cited by applicant]
WO WO2014020502 · 2014 [cited by applicant]
WO WO2014038606 · 2014 [cited by applicant]
WO WO2014100065 · 2014 [cited by applicant]
WO WO2014100071 · 2014 [cited by applicant]
WO WO2014107713 · 2014 [cited by applicant]
WO WO2014108452 · 2014 [cited by applicant]
WO WO2014123418 · 2014 [cited by applicant]
WO WO2014128111 · 2014 [cited by applicant]
WO WO2014134201 · 2014 [cited by applicant]
WO WO2014151863 · 2014 [cited by applicant]
WO WO2015000868 · 2015 [cited by applicant]
WO WO2015006524 · 2015 [cited by applicant]
WO WO2015011084 · 2015 [cited by applicant]
WO WO2015022332 · 2015 [cited by applicant]
WO WO2015015318 · 2015 [cited by applicant]
WO WO2015067770 · 2015 [cited by applicant]
WO WO2015074064 · 2015 [cited by applicant]
WO WO2015097621 · 2015 [cited by applicant]
WO WO2015160845 · 2015 [cited by applicant]
WO WO2015195863 · 2015 [cited by applicant]
WO WO2016050821 · 2016 [cited by applicant]
WO WO2016069578 · 2016 [cited by applicant]
WO WO2016118666 · 2016 [cited by applicant]
WO WO2016146985 · 2016 [cited by applicant]
WO WO2016172134 · 2016 [cited by applicant]
WO WO2016197114 · 2016 [cited by applicant]
WO WO2017011590 · 2017 [cited by applicant]
WO WO2017024318A1 · 2017 [cited by applicant]
WO WO2017024319A1 · 2017 [cited by applicant]
WO WO2017030814 · 2017 [cited by applicant]
WO WO2017079267 · 2017 [cited by applicant]
WO WO2017176957 · 2017 [cited by applicant]
WO WO2017185036 · 2017 [cited by applicant]
Ding et al., Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development, Journal of Medicinal Chemistry, 2013, vol. 56, pp. 5979-5983 (Year: 2013). [cited by examiner]
Schneekloth et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorganic & Medicinal Chemistry Letters, 2008, vol. 18, pp. 5904-5908 (Year: 2008). [cited by examiner]
Albrecht, B., et al., “Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BETA) family as a candidate for human clinical trials”, Journal Med. Chem. 59, 1330-1339 (2016… [cited by applicant]
Allan, GF, et. al., “Therapeutic androgen receptor ligands”, Nuclear Receptor Signaling, 2003, 1, e009 DOI:10.621.01009 9 1-4. [cited by applicant]
Asangani, I.A. et al., “Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer”, Nature, 2014, 510: 278-282. [cited by applicant]
Baratta, M.G. et al., “An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinonoma”, PNAS, 112: 232-237 (2015). [cited by applicant]
Bargagna-Mohan, et al., “Use of Protacs as molecular probes of angiogenesis”, Bioorg Med Chem Left. 15(11) 2005, 2724-2727. [cited by applicant]
Battista, M. J. & Schmidt, M. Fulvestrant for the treatment of endometrial cancer. Expert Opin Investig Drugs 25, 475-483 (2016). [cited by applicant]
Belkina, A.C. et al., “BET domain co-regulators in obesity, inflammation and cancer”, Nat. Rev. Cancer, 12 (2012) 465-477. [cited by applicant]
Boi, M. et al., “The BET Bromodomain inhibitor OTX015 Affects pathogenetic Pathways in Preclinical B-cell Tumor Models and synergizes with Targeted Drugs”, Clin. Cancer Res., (2015) 21(7):1628-1638. [cited by applicant]
Boitano, et al., “Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells”, ScienceSep. 10, 2010: vol. 329, pp. 1345-1348. [cited by applicant]
Bondeson, et al., “Catalytic in vivo protein knockdown by small-molecule Protacs”, National Chem Biol. 11(8) Aug. 2015, 611-617. [cited by applicant]
Bradbury, RH, et. al., “Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer”, Bioorganic & Medicinal Chemistry Letters, 2011, 21: 5442-5445. [cited by applicant]
Brough, et al., “4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer”, J Med Chem. 51(2), Jan. 24, 2008, 196-218. [cited by applicant]
Buckley, DL., et al., Small Molecule Control of Intracellular Protein Levels Through Modulation of the Ubiquitin Proteasome System, Angew Chem Int Ed Engl. Feb. 24, 2014; 53(9): 2312-2330, doi: 10.1002/anie.201307761 (Y… [cited by applicant]
Buckley, et al., “HaloProtacs: use of small molecule Protacs to induce degradation of HaloTag fusion proteins”, ACS Chem Biol. 10(8), 2015, 1831-1837. [cited by applicant]
Carmony, KC, et al., “Protac-Induced Proteolytic Targeting”, Methods Mol. Biol., 2012, vol. 832, pp. 627-638. [cited by applicant]
CAS 155180-53-3 published 1994. [cited by applicant]
CAS 155255-73-5 published 1995. [cited by applicant]
Ceribelli, M. et al., “Blockade of oncongenic IKB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors”, PNAS, 111 (2014) 11365-11370. [cited by applicant]
Chang, et al., “Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294”, Nat Struct Mol Biol. 16(3), Mar. 2009, 312-317. [cited by applicant]
Chapuy, B. et al., “Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma”, Cancer Cell, 24 (2013) 777-790. [cited by applicant]
Chene, P., et al., “Inhibiting the p53-MDM2 interaction: an important target for cancer therapy”, Nat. Rev. Cancer (2003), 3, 102-109. [cited by applicant]
Chung, et al., “Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains”, J Med Chem. 54(11), Jun. 9, 2011, 3827-3838. [cited by applicant]
Corson, et al., “Design and applications of bifunctional small molecules: why two heads are better than one”, ACS Chemical Biology vol. 3 No. 11, pp. 677-692; Nov. 21, 2008. [cited by applicant]
Crews, C. M., “Targeting the undruggable proteome: the small molecules of my dreams”, [cited by applicant]
Cyrus, et al., “Jostling for position: optimizing linker location in the design of estrogen receptor-targeting Protacs”, Chem Med Chem. 5(7), Jul. 5, 2010, 979-985. [cited by applicant]
Cyrus, K. et al., “Impact of Linker Length on the Activity of Protacs,” Mol. Biosyst., 2011, vol. 7, No. 2, pp. 359-364. [cited by applicant]
Cyrus, K. et al., “Two-Headed Protac: An Effective New Tool for Targeted Protein Degradation,” Chembiochem., 2010, vol. 11, pp. 1531-1534. [cited by applicant]
Dawson, et al., “Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukemia”, Nature 478, Oct. 2, 2011, 529-533. [cited by applicant]
Delmore, J.E. et al., “BET Bromodomain inhibition as a therapeutic strategy to target c-Myc”, Cell, 146 (2011) 904-917. [cited by applicant]
Deroo, B.J., et al., “Estrogen receptors and human disease”, Journal of Clinical Investigation, (2006), vol. 116(3), pp. 561-570. [cited by applicant]
Di, J. et al. “Reactivation of p53 by inhibiting Mdm2 E3 Ligase: a novel antitumor approach”, Current Cancer Drug Targets (2011), 11(8), 987-994. [cited by applicant]
Ding, Q., et al., Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development, J. Med. Chem. 2013, 56, 5979-5983, dx.doi.org/10.1021/jm400487c (Year: 2013). [cited by applicant]
Dixon, S. J. et al., “Identifying druggable disease-modifying gene products”,. Curr Opin Chem Biol 13, 549-555, doi:S1367-5931(09)00107-0 [pii] 10.1016/j.cbpa.2009.08.003 (2009). [cited by applicant]
Filippakopoulos, et al., “Selective inhibition of BET bromodomains”, Nature 468, Dec. 23, 2010, 1067-1073. [cited by applicant]
Finnin, et al., “Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors”, Nature 401, Sep. 9, 1999, 188-193. [cited by applicant]
Gangjee. A. et al . , “The contribution of a 2-amino group on receptor tyrosine kinase inhibition and antiangiogenic activity in 4 anilinosubstituted pyrrolo [2,3-d] pyrimidines”, Bioorganic & Medicinal Chemistry Letter… [cited by applicant]
Golub, et al., “Molecular classification of cancer: class discovery and class prediction by gene expression monitoring”, Science 286, 531-537 (1991). [cited by applicant]
Gosink, M et al., “Redirecting the specificity of ubiquitination by modifying ubiquitin-conjugating enzymes”, Pro. Natl. Acad Sci, vol. 92, pp. 9117-9121, 1995. [cited by applicant]
Guo C., et. al, “Design of oxobenzimidazoles and oxindoles as novel androgen receptor antagonists”, Bioorganic & Medicinal Chemistry Letters, 2012, 22:2572-2578. [cited by applicant]
Gustafson, et al., “Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging”, Agnew Chem Int Ed., 54: 9659-9662 (2015). [cited by applicant]
Haupt, Y. et al., “Mdm2 promotes the rapid degradation of p53”, Nature 387, 296-299 (1997). [cited by applicant]
Hewings, et al., “3,5-Dimethylisoxazoles Act as Acetyllysine-mimetic Bromodomain”, J Med Chem. 54(19), Oct. 13, 2011, 6761-6770. [cited by applicant]
Hines, J., et al., “Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoProtacs”, Proc Natl Acad Sci USA 110, 8942-8947 (2013). [cited by applicant]
Hoffmann, J. et al. Characterization of New Estrogen Receptor Destabilizing Compounds: Effects on Estrogen-Sensitive and Tamoxifen-Resistant Breast Cancer. JNCI Journal of the National Cancer Institute 96, 210-218 (2004… [cited by applicant]
Huang, et al., (2016) “Drugging the undruggables: exploring the ubiquitin system for drug development.” [cited by applicant]
Ishikawa, T. et al., “Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold”, Journal of Medici… [cited by applicant]
Jang, E.R. et al., “Targeted Degradation of Proteins by Protacs,” Curr. Protoc. Chem. Biol., 2010, vol. 2, No. 2, pp. 71-87. [cited by applicant]
Jung, M. E. et al “Structure-Activity Relationship for Thioydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC)”, J. Med. Chem. 2010, 53, 2779-2796. [cited by applicant]
Kim, et al., “Heat shock protein as molecular targets for breast cancer therapeutics”, J. Breast Cancer. 14(3), Sep. 2011, 167-174. [cited by applicant]
Knott, Edward (1955). “Compounds containing sulphur chromophores. Part I. The action of bases on heterocyclic sulphide quarternary salts”, Journal of the Chemical Society (resumed). 10.1039/jr9550000916. 949-954) (USPTO… [cited by applicant]
Konecny, G.E., et al., “Activity of the Dual Kinase Inhibitor Lapatinib (GW572016) against HER-2-Overexpressing and Trastuzumab-Treated Breast Cancer Cells”, Cancer Research 66, 1630-1639 (2006). [cited by applicant]
Kurimchak, A. M. et al.,“Resistance to BET Bromodomain Inhibitors Is Mediated by Kinome Reprogramming in Ovarian Cancer”, Cell Reports 16, 1273-1286 (2016). [cited by applicant]
Lai, A.C., et al., “Modular Protac Design for the Degradation of Oncogenic BCR-ABL”, Angew Chem Int Ed Engl 55, 807-810 (2016). [cited by applicant]
Lala, et al., “Role of nitric oxide in tumor progression: Lessons from experimental tumors”, Cancer and Metastasis Reviews 17:91-106 (1998). [cited by applicant]
Lebraud, H., et al., “Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras”, ACS Central Science, 2, 927-934 (2016). [cited by applicant]
Lee, et al., “Targeted Degradation of the Aryl Hydrocarbon Receptor by the Protac Approach: A Useful Chemical Genetic Tool”, ChemBioChem vol. 8, Issue 17, pp. 2058-2062, Nov. 23, 2007. [cited by applicant]
Lelais, G. et al., “Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a novel, potent, and WT sparing covalent inhibitor of oncoge… [cited by applicant]
Levine, et al., Targeting the androgen receptor with steroid conjugates, J. Med. Chem., vol. 57., No. 20. pp. 8224-8237, (2014). [cited by applicant]
Li, Yan, et al., Single Polymer-drug Conjugate Carrying Two Drugs for Fixed-dose Codelivery, Med chem vol. 4(10): 676-683 (2014)-676-683. [cited by applicant]
Liu, et al., “Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a”, J Med Chem. 52(24), Dec. 24, 2009, 7950-7953. [cited by applicant]
Llinas-Brunet, et al., “Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335)”, J Med Chem. 53(17), Sep. 9, 2010, 6466-6476. [cited by applicant]
Lou, KJ., Protac the protein, Lou, K.-J. Sci BX 5(20); doi:10.1038/scibx.2012.514, Published online May 17, 2012 (Year: 2012). [cited by applicant]
Lountos, et al., “Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy”, J Struct Bio1.176(3), Dec. 2011, 292-301. [cited by applicant]
Loven, J. et al., “Selective Inhibition of Tumor Oncogenes by Disruption of Super Enhancers”, Cell, 153 (2013) 320-334. [cited by applicant]
Lu, et al., “Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4”, Chem Biol 22(6), 2015, 755-763. [cited by applicant]
Martin-Kohler, A. et al . , “Furo [2,3-d] pyrimidines and Oxazolo [5,4-d] pyrimidines as Inhibitors of Receptor Tyrosine Kinases (RTK)”, He I vet ica Chimica Act a , 2004, vol. 87, No. 4, pp. 956-975. [cited by applicant]
Medline Plus Trusted Health Information for You, www.nlm.nih.gov/medlineplus/cancer.html pp. 1-10, (2007). [cited by applicant]
Mehellou, Y., De Clercq E., “Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go?”, J Med Chem. Jan. 28, 2010;53(2):521-538. doi: 10.1021/jm900492g. Review. PubMed PMID: 19785437. [cited by applicant]
Mertz, J.A. et al., “Targeting MYC dependence in cancer by inhibiting BET bromodomains”, PNAS, 108 (2011) 16669-16674. [cited by applicant]
Millan,—et al “Design and Synthesis of Inhaled p38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease”, J Med Chem.54(22), Nov. 24, 2011, 7797-7814. [cited by applicant]
Miyazaki, M., et al., “Discovery of DS-5272 as a promising candidate: a potent and orally active p53-MDM2 interaction inhibitor”, Bioorg. Med. Chem. Lett. (2015) 23, 2360-2367. [cited by applicant]
Mohler, M.L., et al., Androgen receptor antagonists: a patent review (2008-2011), Expert Opinion on Therapeutic Patents, vol. 22, No. 5. pp. 541-565, (2012). [cited by applicant]
Neklesa, T.K., et al., “Chemical biology: Greasy tags for protein removal”, Nature 487, 308-309 (2012). [cited by applicant]
Neochoritis, et al., Chapter 12, p53-MDM2 and MDMX Antagonists, Annual Reports in Medicinal Chemistry, vol. 49, pp. 167-187 (2014). [cited by applicant]
Nicodeme, et al., “Suppression of inflammation by a synthetic histone mimic”, Nature 468, Dec. 23, 2010, 1119-1123. [cited by applicant]
Noel, J. Kay, “Abstract C244: ' Development of the BET Bromodomain inhibitor OTX015”, Mol Cancer Ther 2013; 12(11 Suppl); C244 1-4. [cited by applicant]
Pepe, A. et. al., “Synthesis and structure-activity relationship studies of novel dihydropyridones as androgen receptor modulators”, J. Med. Chem. 2013, 56, 8280-8297. [cited by applicant]
Puissant, A. et al., “Targeting MYCN in neuroblastoma by BET bromodomain inhibition”, Cancer discovery, 3 (2013) 308-323. [cited by applicant]
Puppala, D. et al., “Development of an Aryl Hydrocarbon Receptor Antagonist Using the Proteolysis-Targeting chimeric Molecules Approach: A Potential Tool for Chemoprevention,” Mol. Pharmacol., 2008, vol. 73, No. 4, pp. … [cited by applicant]
Raina, K., et al., “Protac-induced BET protein degradation as a therapy for castration-resistant prostate cancer”, Proc Natl Acad Sci USA 113, 7124-7129 (2016). [cited by applicant]
Raina, K., et al., Chemical Inducers ofTargeted Protein Degradation, The Journal of Biological Chemistry vol. 285, No. 15, pp. 11057-11060, Apr. 9, 2010 (Year: 2010). [cited by applicant]
Rew, Y, et al., “Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction”, J Med Chem. Dec. 26, 2014;57(24):10499-10511. doi: 10.1021/jm501550p. Epub Dec. 4, 2014. PubMed P… [cited by applicant]
Richters, A., et al., “Identification and further development of potent TBK1 inhibitors”, ACS Chemical Biology, vol. 10, No. 1, Jan. 16, 2015, pp. 289-298 (2015). [cited by applicant]
Robertson, J. F. R. Fulvestrant (Faslodex)—how to make a good drug better. Oncologist 12, 774-784 (2007). [cited by applicant]
Rodriguez-Gonzalez, et al., “Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer”, Oncogene. 27(57), Dec. 4, 2008, 7201-7211. [cited by applicant]
Rotili, D., et al., “Photoactivable peptides for identifying enzyme-substrate and protein-protein interactions”, Chem Commun (Carob) 47(5), Feb. 2011, 1488-1490. [cited by applicant]
Rusch, M., et al., “Identification of Acyl Protein Thioesterases 1 and 2 as the Cellular Targets of the Ras-Signaling Modulators Palmostatin B amd M”, Angew. Chem. Int. Ed., 50: 9838-9842. doi:10.1002/anie.201102967 (An… [cited by applicant]
Sakamoto, et al., “Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation”, Mol Cell Proteomics. 2(12), Dec. 2003, 1350-1358. [cited by applicant]
Sakamoto, et al., “Protacs: chimeric molecules that target proteins to the Skp 1-Cullin-F box complex for ubiquitination and degradation”, Proc Natl Acad Sci U S A.98(15), Jul. 17, 2001, 8554-8559. [cited by applicant]
Scagliotti, G., et al., “Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or … [cited by applicant]
Schenkel, et al., “Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors”, J Med Chem.54(24), Dec. 22, 2011, 8440-8450. [cited by applicant]
Schneekloth, et al., “Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation”, J Am Chem Soc. 126(12), Mar. 31, 2004, 3748-3754. [cited by applicant]
Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908. [cited by applicant]
Sequist, L.V., et al., “Randomized Phase II Study of Erlotinib Plus Tivantinib Versus Erlotinib Plus Placebo in Previously Treated Non-Small-Cell Lung Cancer”, Journal of Clinical Oncology 29, 3307-3315 (2011). [cited by applicant]
Smith, et al., “Targeted Intracellular Protein Degradation Induced by a Small Molecule: En Route to Ghemical Proteomics”, Bioorg Med Chem Lett. 18(22), Nov. 15, 2008, 5904-5908. [cited by applicant]
Stuhlmiller, Timothy J., et al., “Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains”, Cell Reports 11, 390-404 (2015). [cited by applicant]
Suh, N. et al. Arzoxifene, a new selective estrogen receptor modulator for chemoprevention of experimental breast cancer. Cancer Res. 61, 8412-8415 (2001). [cited by applicant]
Sun, et al., Potent Bivalent Smac, Mimetics: effect of the linker on binding to inhibitor of apoptosis proteins (IAPs) and Anticancer Activity, J. Med. Chem. 2011, 54, 3306-3318. [cited by applicant]
Toure, et al., (2016) “Small-Molecule Protac: New Approaches to Protein Degradation.” [cited by applicant]
Vallee, et al., “Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo [4,5-c] Pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone”, J Med Chem. 54(20), Oct. 27,… [cited by applicant]
Van Eis, et al., “2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes”, Bioorg Med Chem Lett.21(24), Dec. 15, 2011, 7367-7372. [cited by applicant]
Vassilev, et al., “In vivo activation of the p53 pathway by small-molecule antagonists of MDM2”, Science 303, Feb. 6, 2004, 844-848. [cited by applicant]
Vazquez, A. et al., “The genetics of the p53 pathway, apoptosis and cancer therapy”, Nat. Rev. Drug. Dis., 7, 979-982 (2008). [cited by applicant]
Vu, B. et al. “Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development”, ACS Med. Chem. Lett. (2013) 4, 466-469. [cited by applicant]
Wang, C. et al. Estrogen induces c-myc gene expression via an upstream enhancer activated by the estrogen receptor and the AP-1 transcription factor. Mol. Endocrinol. 25, 1527-1538 (2011). [cited by applicant]
Wang, S., et al. “Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 inhibitors) in clinical trials for cancer treatment”, J. Med. Chem. (2015) 58, 1038-1052. [cited by applicant]
Wang, S., et al. “Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhabitation”, PNAS USA (2008) 105, 3933-3938. [cited by applicant]
Weir, H. M. et al. AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models. Cancer Res. 76, 3307-3318 (2016). [cited by applicant]
Willson, T.M. et al., “3-[4-(1,2-Diphenylbut-1-Enyl)Pheny1] Acrylic Acid: A non-steroidal estrogen with functional selectivity for bone over uterus in rats”, Journal of Medicinal Chemistry, American Chemical Society, US… [cited by applicant]
Winter, et al., “Phthalimide Conjugation as a strategy for in vivo target protein degradation”, Science, 2015 vol. 348 (6241), pp. 1376-1381 [Pub online: May 21, 2015]. [cited by applicant]
Wright, et al., “Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms”, Chem Biol. 11 (6), Jun. 2004, 775-785. [cited by applicant]
Zengerle, et al., “Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4” ACS Chemical Biology, Jun. 2, 2015, vol. 10, pp. 1770-1777. [cited by applicant]
Zhang B.et al., “Small-molecule MDM2-p53 inhibitors: recent advances”, Future Med. Chem. (2015) 7, 631-645. [cited by applicant]
Zhang, D. et al., “Targeted Degradation of Proteins by Small Molecules: A Novel Tool for Functional Proteomics,” comb Chem. High Throughput Screen., 2004, vol. 7, No. 7, pp. 689-697. [cited by applicant]
Zillhardt, M., et al., “Foretinib (GSK1363089), an Orally Available Multikinase Inhibitor of c-Met and VEGFR-2, Blocks Proliferation, Induces Anoikis, and Impairs Ovarian Cancer Metastasis”, Clinical Cancer Research 17,… [cited by applicant]
U.S. Appl. No. 15/206,497, filed Jul. 11, 2016, US 2017-0008904 A1. [cited by applicant]