IP Library › Granted Patent US 12,551,487
Granted Patent B2
US 12,551,487 · App. 17/612,709 · Granted Feb 17, 2026

PI3K inhibitor for use in the therapy of b cell lymphoma

Inventor: Penelope Ward (Oxfordshire, GB)
Assignee: Convalife (Shanghai) Co. Limited
A61K31/5386A61K45/06A61P35/00C07D519/00
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Quick Facts
Patent No.
US 12,551,487
App. No.
17/612,709
Granted
Feb 17, 2026
Kind
B2
Abstract

The present invention relates to a compound of formula (I), or its pharmaceutically acceptable salt. The compound, or its pharmaceutically acceptable salt, is useful as a PI3K inhibitor and therefore in therapy. In particular, the compound, or its pharmaceutically acceptable salt, has utility in the treatment of B cell lymphoma.

Claims (23)

1 . A method of treating B cell lymphoma in a patient comprising administering to the patient a therapeutically effective amount of a compound having the structure:

wherein the B cell lymphoma is treated in the patient.

2 . The method of claim 1 , for treating or preventing diffuse large B-cell lymphoma, follicular non-Hodgkin lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukaemia, primary central nervous system lymphoma, primary intraocular lymphoma or Waldenstrom macroglobulinemia.

3 . The method of claim 1 , for treating or preventing B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia, small lymphocytic lymphoma or Waldenstrom macroglobulinemia.

4 . The method of claim 1 , wherein the compound is administered in a total dose of between 50 and 400 mg daily.

5 . The method of claim 1 , wherein the compound is administered once daily or twice daily.

6 . The method of claim 1 , wherein the compound is administered to a patient who has already received conventional first-line treatment, comprising one or more of conventional cytotoxic agents selected from the group consisting of, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an immunomodulatory imide drug, a proteasome, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints, bi-specific T-cell engaging therapies, and cellular therapies; and combinations thereof.

7 . A method of treating B cell lymphoma in a patient in need thereof, comprising: administering an effective amount of 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, wherein the B cell lymphoma is treated in the patient.

8 . A method of treating advanced or metastatic B cell lymphoma in a patient in need thereof, wherein the patient has progression of the B cell lymphoma after previous administration of another therapy, comprising: administering an effective amount of 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, wherein the advanced or metastatic B cell lymphoma is treated in the patient.

9 . The method of claim 8 , wherein the previous administration of another therapy is a therapy for advanced or metastatic B cell lymphoma.

10 . The method of claim 8 , wherein the previous administration of another therapy is an administration of another chemotherapeutic agent.

11 . The method of claim 10 , wherein the previous administration of a chemotherapeutic agent includes conventional cytotoxic agents, a CD20 antibody with or without a drug conjugate, a BCL2 inhibitor, a BTK inhibitor, an immunomodulatory imide drug, a proteasome inhibitor, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints, bi-specific T-cell engaging therapies, or cellular therapies.

12 . The method of claim 7 , wherein administering an effective amount of 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, comprises orally administering a total daily dose of about 200 mg to about 400 mg of the 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene.

13 . The method of claim 7 , wherein administering an effective amount of 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, comprises orally administering, once or twice daily, about 200 mg to about 400 mg of the 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene.

14 . The method of claim 7 , wherein the patient has a histological or cytological diagnosis of B cell lymphoma.

15 . The method of claim 7 , wherein administering an effective amount of 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, comprises a 28 to 35 day cycle, wherein 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is administered daily or twice a to the patient for 3 or 4 weeks, and 1 week no 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene is administered.

16 . The method of claim 1 , further comprising administering to the patient a therapeutically effective amount of at least one second agent selected from the group consisting of conventional cytotoxic agents, a CD20 antibody with or without a drug conjugate, obinutuzumab or ibritumomab, a BCL2, a BTK inhibitor, a MEK inhibitor, an immunomodulatory imide drug such as, a proteasome, radiation therapy, agents that modulate anti-tumour immunity including agents modulating immune checkpoints, bi-specific T-cell engaging therapies, or cellular therapies.

17 . The method of claim 16 , wherein the administration of the compound and the at least one second agent is separate, sequential or simultaneous.

18 . The method of claim 1 , wherein the compound is provided as its succinate salt.

19 . The method of claim 4 , wherein the compound is administered in a total dose of between 200 and 400 mg daily.

20 . The method of claim 19 , wherein the compound is administered in a total dose of 200 mg daily.

21 . The method of claim 12 , wherein administering an effective amount of 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, comprises orally administering a total daily dose of 200 mg of the 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene.

22 . The method of claim 13 , wherein administering an effective amount of 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene or a pharmaceutically acceptable salt thereof, comprises orally administering, once or twice daily, 200 mg of the 4-(1H-Indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 5, 2022
From: KARUS THERAPEUTICS LIMITED
To: CONVALIFE (SHANGHAI) CO. LIMITED
Reel/Frame 061315/0660 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 4, 2022
From: WARD, PENELOPE
To: KARUS THERAPEUTICS LIMITED
Reel/Frame 058885/0232 →
Priority Claims (1)
GB 1909468 · Jul 1, 2019 · national
Continuity (1)
Related Publication 20220273667A1 · Sep 1, 2022
References Cited (143)
US 3491092A · Grigat et al. · 1970 [cited by applicant]
US 4017500A · Mayer et al. · 1977 [cited by applicant]
US 5703075A · Gammill et al. · 1997 [cited by applicant]
US 7182958B1 · Oren et al. · 2007 [cited by applicant]
US 7361662B2 · Rault et al. · 2008 [cited by applicant]
US 8242116B2 · Alexander et al. · 2012 [cited by applicant]
US 8338592B2 · Alexander et al. · 2012 [cited by applicant]
US 8710054B2 · Alexander et al. · 2014 [cited by applicant]
US 8921361B2 · Cmiljanovic et al. · 2014 [cited by applicant]
US 8981087B2 · Shuttleworth et al. · 2015 [cited by applicant]
US 9200007B2 · Shuttleworth et al. · 2015 [cited by applicant]
US 9266879B2 · Shuttleworth et al. · 2016 [cited by applicant]
US 9580442B2 · Shuttleworth et al. · 2017 [cited by applicant]
US 9663487B2 · Shuttleworth et al. · 2017 [cited by applicant]
US 9868749B2 · Alexander et al. · 2018 [cited by applicant]
US 9890174B2 · Alexander et al. · 2018 [cited by applicant]
US 9932343B2 · Alexander et al. · 2018 [cited by applicant]
US 9938290B2 · Shuttleworth et al. · 2018 [cited by applicant]
US 9981987B2 · Shuttleworth et al. · 2018 [cited by applicant]
US 10035785B2 · Shuttleworth et al. · 2018 [cited by applicant]
US 10087179B2 · Alexander et al. · 2018 [cited by applicant]
US 10377764B2 · Shuttleworth et al. · 2019 [cited by applicant]
US 10442815B2 · Shuttleworth et al. · 2019 [cited by applicant]
US 10501478B2 · Shuttleworth et al. · 2019 [cited by applicant]
US 10513530B2 · Shuttleworth et al. · 2019 [cited by applicant]
US 10668077B2 · Shuttleworth et al. · 2020 [cited by applicant]
US 11291669B2 · Shuttleworth et al. · 2022 [cited by applicant]
US 11708378B2 · Shuttleworth et al. · 2023 [cited by applicant]
US 11779586B2 · Shuttleworth et al. · 2023 [cited by applicant]
US 20020151544A1 · Hayakawa et al. · 2002 [cited by applicant]
US 20070135466A1 · Ledeboer et al. · 2007 [cited by applicant]
US 20110201608A1 · Hoffmann et al. · 2011 [cited by applicant]
US 20120178737A1 · Shuttleworth et al. · 2012 [cited by applicant]
US 20130109688A1 · Shuttleworth et al. · 2013 [cited by applicant]
US 20140163033A1 · Bernal Anchuela et al. · 2014 [cited by applicant]
US 20150080395A1 · Shuttleworth et al. · 2015 [cited by applicant]
US 20160108057A1 · Shuttleworth et al. · 2016 [cited by applicant]
US 20160113932A1 · Stern et al. · 2016 [cited by applicant]
US 20160347771A1 · Shuttleworth et al. · 2016 [cited by applicant]
US 20180009826A1 · Shuttleworth et al. · 2018 [cited by applicant]
US 20180072699A1 · Shuttleworth et al. · 2018 [cited by applicant]
US 20180235974A1 · Shuttleworth et al. · 2018 [cited by applicant]
US 20180243313A1 · Shuttleworth et al. · 2018 [cited by applicant]
US 20180243317A1 · Shuttleworth et al. · 2018 [cited by applicant]
US 20180244685A1 · Shuttleworth et al. · 2018 [cited by applicant]
US 20180244686A1 · Shuttleworth et al. · 2018 [cited by applicant]
US 20190040079A1 · Shuttleworth et al. · 2019 [cited by applicant]
US 20190092790A1 · Shuttleworth et al. · 2019 [cited by applicant]
US 20200354378A1 · Shuttleworth et al. · 2020 [cited by applicant]
US 20210069200A1 · Shuttleworth et al. · 2021 [cited by applicant]
US 20210275537A1 · Shuttleworth et al. · 2021 [cited by applicant]
US 20220041624A1 · Shuttleworth et al. · 2022 [cited by applicant]
EP 1277738A1 · 2003 [cited by applicant]
EP 1724267A1 · 2006 [cited by applicant]
GB 1402431A · 1975 [cited by applicant]
WO WO200108356A1 · 2001 [cited by applicant]
WO WO0183456A1 · 2001 [cited by applicant]
WO WO0202551A1 · 2002 [cited by applicant]
WO WO02085400A1 · 2002 [cited by applicant]
WO WO2004006846A2 · 2004 [cited by applicant]
WO WO2004043956A1 · 2004 [cited by applicant]
WO WO2005117889A1 · 2005 [cited by applicant]
WO WO2006046035A1 · 2006 [cited by applicant]
WO WO2006127587A1 · 2006 [cited by applicant]
WO WO2007084667A2 · 2007 [cited by applicant]
WO WO2007122410A1 · 2007 [cited by applicant]
WO WO2007127183A1 · 2007 [cited by applicant]
WO WO2008064018A1 · 2008 [cited by applicant]
WO WO2008076447A2 · 2008 [cited by applicant]
WO WO2008094992A2 · 2008 [cited by applicant]
WO WO2008121257A1 · 2008 [cited by applicant]
WO WO2008145688A2 · 2008 [cited by applicant]
WO WO2008150827A1 · 2008 [cited by applicant]
WO WO2010015520A1 · 2010 [cited by applicant]
WO WO2010037765A2 · 2010 [cited by applicant]
WO WO2010052569A2 · 2010 [cited by applicant]
WO WO2011012883A1 · 2011 [cited by applicant]
WO WO2011021038A1 · 2011 [cited by applicant]
WO WO2011079231A1 · 2011 [cited by applicant]
WO WO2011135351A1 · 2011 [cited by applicant]
WO WO2013014448A1 · 2013 [cited by applicant]
WO WO2013017480A1 · 2013 [cited by applicant]
WO WO2013132270A1 · 2013 [cited by applicant]
WO WO2014081718A1 · 2014 [cited by applicant]
WO WO2015054099A1 · 2014 [cited by applicant]
WO WO2014181137A1 · 2014 [cited by applicant]
WO WO2014210354A1 · 2014 [cited by applicant]
WO WO2015054355A1 · 2015 [cited by applicant]
WO WO2015121657A1 · 2015 [cited by applicant]
WO WO2016075130A1 · 2016 [cited by applicant]
WO WO2017029514A1 · 2017 [cited by applicant]
WO WO2017029517A1 · 2017 [cited by applicant]
WO WO2017029518A1 · 2017 [cited by applicant]
WO WO2017029519A1 · 2017 [cited by applicant]
WO WO2017029521A1 · 2017 [cited by applicant]
WO WO2021001650A1 · 2021 [cited by applicant]
Alvarez-Rua et al., “Multiple Hydrogen Bonds and Tautomerism in Naphthyridine Derivatives”, New J. Chem. 28, 700-07 (2004). [cited by applicant]
Ameriks et al., “Small Molecule Inhibitors of Phosphoinositide 3-Kinase (PI3K) δ and γ”, Current Topics in Medicinal Chemistry, 2009, vol. 9, No. 8, pp. 738-753. [cited by applicant]
Annex to Form PCT/ISA/206 Communication relating to the results of the partial international search for International Application No. PCT/GB2016/052571 mailed Nov. 9, 2016 (4 pages). [cited by applicant]
Baldev Singh et al., “Novel cAMP PDE III Inhibitors: 1,6-Naphthyridin-2(18)-ones”, Journal of Medicinal Chemistry, American Chemical Society, 35(26): 5858-4865, Jan. 1, 1992, New York. [cited by applicant]
Brachmann, S. et al. PI3K and mTOR inhibitors—a new generation of targeted anticancer agents. Current Opinion in Cell Biology. 2009, 21, 194-198. [cited by applicant]
Bianchi et al. (2014) “Team Work Matters: Dual Inhibition Puts Non-Hodgkin Lymphoma Under Siege,” [cited by applicant]
Bodo et al. (2012) “Abstract 3714; The PI3K Inhibitor GS-1101 (CAL-101) Synergistically Potentiates HDAC-Induced Proliferation Inhibition and Apoptosis Through the Activation of JNK in Lymphoma Cells,” [cited by applicant]
CAS Registry Nos. 1214438-02-4 and 1214393-37-9 (Mar. 25, 2010). [cited by applicant]
Cohen et al., Current Opinion in Chemical Biology, 3, 459-465, 1999. [cited by applicant]
D.A. Kovalskiy et al., “Synthesis of 7-(3-piperidyl)[1,6]naphthyridine and 7-(4-piperidyl)[1,6]naphthyridine”, Chemistry of Heterocyclic Compounds, 45(9): 1053-1057, Nov. 24, 2009. [cited by applicant]
Database Chemcats [Online], Chemical Abstracts Service, Apr. 22, 2011, Columbus, Ohio. [cited by applicant]
Erik L. Meredith et al., “Identification of Orally Available Naphthyridine Protein Kinase D Inhibitors”, Journal of Medicinal Chemistry, 53(15): 5400-5421, Aug. 12, 2010. [cited by applicant]
European Search Report for EP application No. 18202398.6 dated Feb. 15, 2019 (5 pages). [cited by applicant]
Fabbro et al. Pharmacology & therapeutics 93, 79-98, 2002. [cited by applicant]
Golub et al., Science, 286, 531-537, 1999. [cited by applicant]
Hayakawa, et al., “Synthesis and Biological Evaluation of Pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine Derivatives as Novel PI3 Kinase p110α Inhibitors” Bioorganic & Medicinal Chemistry Letters, 2007, vol. 17, pp. 2438-2442. [cited by applicant]
Hollebecque A et al., (2014), ‘A Phase Ib Trial of LY2584702 Tosylate, a p70 S6 Inhibitor, in Combination with Erlotinib or Everolimus in Patients with Solid Tumours,’ Eur J Cancer, 50(5):876-84. [cited by applicant]
International Preliminary Report on Patentability and Written Opinion of the International Searching Authority for PCT/GB2010/051221 dated Jan. 31, 2012 (7 pages). [cited by applicant]
International Preliminary Report on Patentability and Written Opinion of the International Searching Authority for PCT/GB2010/051370 dated Feb. 21, 2012 (6 pages). [cited by applicant]
International Preliminary Report on Patentability and Written Opinion of the International Searching Authority for PCT/GB2011/050824 dated Nov. 6, 2012 (7 pages). [cited by applicant]
International Preliminary Report on Patentability and Written Opinion of the International Searching Authority for PCT/GB2013/050583 dated Sep. 9, 2014 (6 pages). [cited by applicant]
International Preliminary Report on Patentability and Written Opinion of the International Searching Authority for PCT/GB2015/050396 dated Aug. 16, 2016 (6 pages). [cited by applicant]
International Search Report and Written Opinion of the International Searching Authority for PCT/GB2020/051582 mailed Oct. 8, 2020 (10 pages). [cited by applicant]
International Search Report of the International Searching Authority for PCT/GB2010/051221 dated Oct. 7, 2010 (4 pages). [cited by applicant]
International Search Report of the International Searching Authority for PCT/GB2010/051370 dated Nov. 9, 2010 (4 pages). [cited by applicant]
International Search Report of the International Searching Authority for PCT/GB2011/050824 dated Jul. 12, 2011 (5 pages). [cited by applicant]
International Search Report of the International Searching Authority for PCT/GB2013/050583 dated May 6, 2013 (4 pages). [cited by applicant]
International Search Report of the International Searching Authority for PCT/GB2015/050396 mailed Mar. 25, 2015 (3 pages). [cited by applicant]
International Search Report of the International Searching Authority for PCT/GB2016/052571 mailed Feb. 23, 2017 (6 pages). [cited by applicant]
Lin L. et al., (2014), ‘Dual Targeting of Glioblastoma Multiforme with a Proteasome Inhibitor (Velcade) and a Phosphatidylinositol 3-Kinase Inhibitor (ZSTK474),’ Int J Oncol, 44(2):557-62. [cited by applicant]
Liu, Q. et al. mTOR mediated anti-cancer drug discovery. Drug Discovery Today: Therapeutic Strategies. 2009, 6 (2), 47-55. [cited by applicant]
Mass, R. D., Int. J. Radiation Oncology Bio. Phys. vol. 58 (3): 932-940, 2004. [cited by applicant]
Notification of the Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration, (form ISA/220), International Application No. PCT/GB2016/052575 , … [cited by applicant]
Notification of the Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration, (form ISA/220), International Application No. PCT/GB2016/052577 , … [cited by applicant]
Notification of the Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration, (form ISA/220), International Application No. PCT/GB2016/052578 , … [cited by applicant]
Notification of the Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration, (form ISA/220), International Application No. PCT/GB2016/052581 , … [cited by applicant]
Saifuddin, M. et al., “Water-Accelerated Cationic pi-(7-endo) cyclisation: Application to Indole-Based Peri-Annulated Polyheterocycles.” European Journal of Organic Chemistry, 2010, 26, 5108-5117. [cited by applicant]
Schröder E et al., ‘Arzneimittel Chemie Passage,’ [cited by applicant]
Shuttleworth, S. J. et al. Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors. Current Medicinal Chemistry, 2011, 18, 2686-2714. [cited by applicant]
Somei et al., “Boronation-Thallation, A New Approach to the Synthesis of Indoles Having Aryl and/or a Heteroaryl Substituent at the 4-Position.” Chem. Pharm. Bull. 1986, 34, 3971-3. [cited by applicant]
Tao J et al., (2013), ‘Combined Treatment of BTK and PI3K Inhibitors Synergistically Disrupts BCR-Signaling, Overcomes Microenvironment-Mediated Survival and Drug Resistance in Mantle Cell Lymphoma,’ Proceedings of the … [cited by applicant]
Verheijen et al., “Phosphatidylinositol 3-kinase (PI3K) inhibitors as anticancer drugs”, Drugs of the Future, 2007, vol. 32, No. 6, pp. 537-547. [cited by applicant]
Written Opinion of the International Searching Authority for PCT/GB2016/052571 dated Feb. 23, 2017 (9 pages). [cited by applicant]
Yamada T et al., (2013) ‘A Novel HDAC Inhibitor OBP-801 and a PI3K Inhibitor LY294002 Synergistically Induce Apoptosis via the Suppression of Survivin and XIAP in Renal Cell Carcinoma,’ Int J Oncol, 43(4):1080-6. [cited by applicant]
Zhao, X. et al. Discovery of novel Bruton's tyrosine kinase (BTK) inhibitors bearing a pyrrolo[2,3-d]pyrimidine scaffold. Bioorganic and Medicinal Chemistry, 23, 2015, 891-901. [cited by applicant]
Zhong H et al., (2013) ‘Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models,’ PLoS One, 8(10):e77243. [cited by applicant]
Zhou W et al., (2009) Novel Mutant-Selective EGFR Kinase Inhibitors Against EGFR T790M, Nature, 462(7276):1070-4 [NIH Public Access Version]. [cited by applicant]