IP Library › Granted Patent US 12,186,311
Granted Patent B2
US 12,186,311 · App. 18/139,151 · Granted Jan 7, 2025

Antiproliferative compounds and second active agents for combined use

Inventor: Lilly L. Wong (Solana Beach, CA)
Assignee: Celgene Corporation
A61K31/496A61K31/436A61K31/444A61K31/454A61K31/497A61K31/4985A61K31/5025A61K31/506A61K31/517A61K31/519A61K31/52A61K31/551A61K31/573A61K31/69A61K31/706A61K45/06A61P35/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,186,311
App. No.
18/139,151
Granted
Jan 7, 2025
Kind
B2
Abstract

Provided herein are methods of using 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof, in combination with a second active agent for treating, preventing or managing multiple myeloma. The second active agent is one or more of a BTK inhibitor, an mTOR inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an MEK inhibitor, an XPO1 inhibitor, a DOT1L inhibitor, an EZH2 inhibitor, a JAK2 inhibitor, a BRD4 inhibitor, a PLK1 inhibitor, an NEK2 inhibitor, an AURKB inhibitor, a BIRC5 inhibitor, a BET inhibitor, or a DNA methyltransferase inhibitor.

Claims (16)

1. A method of treating multiple myeloma comprising administering to a patient having multiple myeloma a therapeutically effective amount of a compound in combination with a second active agent, wherein the compound is Compound 1 of formula

or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the second active agent is an EZH2 inhibitor; and wherein the EZH2 inhibitor is tazemetostat, 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, UNC1999, CPI-1205, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

2. A method of treating multiple myeloma comprising administering to a patient having multiple myeloma a therapeutically effective amount of a compound in combination with a second active agent, wherein the compound is Compound 2 of formula

or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the second active agent is an EZH2 inhibitor; and wherein the EZH2 inhibitor is tazemetostat, 3-deazaneplanocin A (DZNep), EPZ005687, EI1, GSK126, UNC1999, CPI-1205, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein the compound is Compound 2.

4. The method of claim 2 , wherein the EZH2 inhibitor is tazemetostat.

5. The method of claim 2 , wherein the EZH2 inhibitor is UNC 1999 .

6. The method of claim 2 , wherein the EZH2 inhibitor is CPI-1205.

7. The method of claim 2 , wherein the multiple myeloma is relapsed, refractory or resistant.

8. The method of claim 7 , wherein the multiple myeloma is refractory or resistant to lenalidomide.

9. The method of claim 7 , wherein the multiple myeloma is refractory or resistant to pomalidomide.

10. The method of claim 2 , wherein the multiple myeloma is newly diagnosed multiple myeloma.

11. The method of claim 2 , further comprising administering to the patient an additional active agent.

12. The method of claim 11 , wherein the additional active agent is dexamethasone.

13. The method of claim 11 , wherein the additional active agent is bortezomib.

14. The method of claim 4 , wherein tazemetostat is administered at a dosage of about 800 mg twice daily, about 400 mg twice daily, or about 200 mg twice daily.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 13, 2023
From: SIGNAL PHARMACEUTICALS, LLC
To: CELGENE CORPORATION
Reel/Frame 064249/0667 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 13, 2023
From: WONG, LILLY L.
To: SIGNAL PHARMACEUTICALS, LLC
Reel/Frame 064273/0986 →
Continuity (3)
Division 16737710 · Jan 8, 2020
Provisional Application 62790326 · Jan 9, 2019
Related Publication 20230330086A1 · Oct 19, 2023
References Cited (30)
US 10357489B2 · Alexander et al. · 2019 [cited by applicant]
US 11185543B2 · Alexander et al. · 2021 [cited by applicant]
US 11660297B2 · Wong · 2023 [cited by examiner]
US 20160038495A1 · Kuo et al. · 2016 [cited by applicant]
US 20170232030A1 · Klaus et al. · 2017 [cited by applicant]
US 20230181575A1 · Pierce · 2023 [cited by examiner]
WO WO2019006299A1 · 2019 [cited by applicant]
WO WO2019014100A1 · 2019 [cited by applicant]
Harding et al. EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes. Oncotarget, 2018, vol. 9, (No. 31), pp. 21930-21942. (Year: 2018). [cited by examiner]
Arora et al. EZH2 Inhibitors Are Broadly Eff icacious in Multiple Myeloma As Single Agent and in Combination with Standard of Care Therapeutics. Blood (2016) 128 (22): 5672, p. 1-2. (Year: 2016). [cited by examiner]
Nara et al. Bortezomib Reduces the Tumorigenicity of Multiple Myeloma via Downregulation of Upregulated Targets in Clonogenic Side Population Cells. PLoS One 8(3): e56954, pp. 1-13, 2013. (Year: 2013). [cited by examiner]
Fiskus et al. Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells. Mol Cancer Ther 2006;5(12):3096-3104, Dec. 2006. (Year: 2006). [cited by examiner]
Sehgal et al. FAS-antisense 1 IncRNA and production of soluble versus membrane Fas in B-cell lymphoma. Leukemia (2014) 28, 2376-2387. (Year: 2014). [cited by examiner]
Nath et al., “Transcriptional Control of Mitosis: Deregulation and Cancer”, Frontiers in Endocrinology, 6(60), 1-10 (2015). [cited by applicant]
Delmore et al., “BET bromodomain inhibition as a therapeutic strategy to target c-Myc”, Cell, 146(6), 904-917 (2011). [cited by applicant]
Stewart et al., “The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma”, Experimental Hematology, 39, 330-338 (2011). [cited by applicant]
Franqui-Machin et al., “Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma”, The Journal of Clinical Investigation, 128(7), 2877-2893 (2018). [cited by applicant]
Santo et al., “Anti-myeloma activity of a multi targeted kinase inhibitor, AT9283, via potent Aurora Kinase and STAT3 inhibition either alone or in combination with lenalidomide”, Clinical Cancer Research, 17(10), 3259-… [cited by applicant]
Ito et al., “YM155, a Survivin Suppressant, Induces Cell Death Via Suppression Of c-Myc Expression In Multiple Myeloma Cells. Blood”, 122(21), 1667 (2013). [cited by applicant]
Kiziltepe et al., “5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myelo… [cited by applicant]
Anonymous, “History of changes for study NCT03374085 a safety, PK and efficacy study of CC-92480 in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma,” ClinicalTrials.gov Aug. 23, … [cited by applicant]
Anonymous, “Welcome to the R&D deep dive series multiple myeloma changing the course of human health through bold pursuits in science,” Mar. 24, 2018, pp. 1-108, retrieved from the Internet: URL:https://s24.q4cdn.com/48… [cited by applicant]
Hansen et al., “Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma,” [cited by applicant]
Nooka et al., “Mechanism of action and novel IMiD-based compounds and combinations in multiple myeloma,” [cited by applicant]
Anonymous, ClinicalTrials.gov Identifier: NCT03374085, https://clinicaltrials.gov/ct2/show/NCT03374085, First Posted: Dec. 15, 2017 (2017). [cited by applicant]
Rushworth et al., “BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB,” Cellular Signaling, 25(1): 106-112 (2013). [cited by applicant]
Mezigdomide (CC-92480), Cereblon E3 ubiquitin ligase modulating agent, https://www.medchemexpress.com/cc-92480.html (accessed on Dec. 8, 2021) (2021). [cited by applicant]
Yu et al., “Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via Nf-κB,” Blood, 111(9): 4617-4626 (2008). [cited by applicant]
Birabresib, https://pubchem.ncbi.nlm.nih.gov/compound/9936746, created on Oct. 25, 2006. [cited by applicant]
Riveiro et al., “OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations”, Oncotarget, 7(51): 84675-84687 (2016). [cited by applicant]