Combination therapy of transcription inhibitors and kinase inhibitors

1. A method of treating a solid tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of:

a transcription inhibitor; and

a kinase inhibitor, wherein the kinase inhibitor is an epidermal growth factor receptor (EGFR) inhibitor; wherein:

the solid tumor is bladder cancer, lung cancer, esophageal cancer, skin cancer, or stomach cancer;

the transcription inhibitor is of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, or isotopically labeled compound thereof, wherein:

Ring A is an optionally substituted heteroaryl ring of the formula:

one or two instances of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , and V 9 are independently N or NR A1 , the remaining instances of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , and V 9 are independently C or CR A2 ;

each instance of R A1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group;

each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R A2a groups are joined to form an optionally substituted heterocyclic ring;

or any two of R A1 , R A2 , and R A2a groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;

Ring B is of the formula:

R B1 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R B1a groups are joined to form an optionally substituted heterocyclic ring;

W B is N or CR B2 , wherein R B2 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR B2a , —N(R B2a ) 2 , and —SR B2a , wherein each occurrence of R B2a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R B2a groups are joined to form an optionally substituted heterocyclic ring;

or R B1 and R B2 are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl ring;

X is —NR x —;

L 2 is —NR L2a C(═O)—, —C(═O)NR L2a —, —S(═O) 2 NR L2a —, or —NR L2a S(═O) 2 —, wherein each instance of R L2a is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group;

each instance of R C is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R C1 groups are joined to form an optionally substituted heterocyclic ring;

n is 0, 1, 2, 3, or 4;

each instance of R D is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R D1 groups are joined to form an optionally substituted heterocyclic ring;

p is 0, 1, 2, 3, or 4;

R E is of the formula:

R E and L 2 are para or meta to each other;

L 3 is a bond, —O—, —S—, —NR L3a —, or an optionally substituted C 1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR L3a —, —NR L3a C(═O)—, —C(═O)NR L3a —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR L3a C(═S)—, —C(═S)NR L3a —, trans-CR L3b ═CR L3b —, cis-CR L3b ═CR L3b —, —C≡—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR L3a —, or —NR L3a S(═O) 2 —, wherein each instance of R L3a is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R L3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R L3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , and —SR E1a , wherein each occurrence of R E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a groups are joined to form an optionally substituted heterocyclic ring;

R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a groups are joined to form an optionally substituted heterocyclic ring;

R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a groups are joined to form an optionally substituted heterocyclic ring;

or R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; and

Y is O, S, or NR E5 , wherein R E5 is hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group;

provided that the transcription inhibitor and the kinase inhibitor are not the same.

2. The method of claim 1 , wherein the transcription inhibitor is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, or isotopically labeled compound thereof.

3. The method of claim 1 , wherein:

Ring A is an optionally substituted heteroaryl ring of the formula:

4. The method of claim 1 , wherein each instance of R A1 is independently selected from the group consisting of hydrogen and optionally substituted alkyl.

5. The method of claim 1 , wherein each instance of R A2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted aryl.

6. The method of claim 1 , wherein R B1 is selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.

7. The method of claim 1 , wherein W B is CR B2 .

8. The method of claim 7 , wherein R B2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, or —OR B2a .

9. The method of claim 1 , wherein R X is hydrogen.

10. The method of claim 1 , wherein each instance of R C is independently selected from the group consisting of hydrogen, halogen, and optionally substituted alkyl.

11. The method of claim 1 , wherein L 2 is —NR L2a C(═O)—.

12. The method of claim 11 , wherein R L2a is hydrogen.

13. The method of claim 1 , wherein each instance of R D is hydrogen.

14. The method of claim 1 , wherein R E3 is selected from the group consisting of hydrogen and optionally substituted alkyl.

15. The method of claim 1 , wherein R E3 is selected from the group consisting of —CH 2 OR E3a and —CH 2 N(R E3a ) 2 .

16. The method of claim 1 , wherein the transcription inhibitor is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, or isotopically labeled compound thereof.

17. The method of claim 1 , wherein the EGFR inhibitor is erlotinib, lapatinib, AZD8931, WZ4002, panitumumab, vandetanib, icotinib, afatinib, brigatinib, CO-1688, AZD-4769, poziotinib, CUDC-101, S-222611, AC-480, imgatuzumab, sapitinib, TAS-2913, theiiatinib, XGFR-2421, HM-61713B, epitinib, NRC-2694, MLBS-42, JRP-890, cetuximab, AL-6802, TAK-285, BGB-102, AEE788, gefitinib, DMS-3008, TX-2036, KI-6783, or KI-6896, or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the EGFR inhibitor is erlotinib, or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the EGFR inhibitor is afatinib, brigatinib, cetuximab, gefitinib, icotinib, lapatinib, panitumumab, or vandetanib, or a pharmaceutically acceptable salt thereof.

20. The method of claim 2 , wherein the EGFR inhibitor is erlotinib, lapatinib, or WZ4002, or a pharmaceutically acceptable salt thereof.

21. The method of claim 2 , wherein the EGFR inhibitor is afatinib, brigatinib, cetuximab, gefitinib, icotinib, lapatinib, panitumumab, vandetanib, or neratinib, or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the solid tumor is lung cancer, esophageal cancer, or skin cancer.

23. The method of claim 1 , wherein the solid tumor is associated with a mutation in an epidermal growth factor receptor (EGFR) gene.

24. The method of claim 23 , wherein the mutation is a T790M mutation, L858R mutation, or exon 19 deletion mutation.

25. The method of claim 1 , wherein the solid tumor is esophageal cancer.

26. The method of claim 1 , wherein the solid tumor is skin cancer.