Combination therapy of transcription inhibitors and kinase inhibitors

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 V1, V2, V3, V4, V5, V6, V7, V8, and V9 are independently N or NRA1, the remaining instances of V1, V2, V3, V4, V5, V6, V7, V8, and V9 are independently C or CRA2;
• each instance of RA1 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 RA2 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, —ORA2a, —N(RA2a)2, and —SRA2a, wherein each occurrence of RA2a 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 RA2a groups are joined to form an optionally substituted heterocyclic ring;
• or any two of RA1, RA2, and RA2a 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:
• RB1 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, —ORB1a, —N(RB1a)2, and —SRB1a, wherein each occurrence of RB1a 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 RB1a groups are joined to form an optionally substituted heterocyclic ring;
• WB is N or CRB2, wherein RB2 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, —ORB2a, —N(RB2a)2, and —SRB2a, wherein each occurrence of RB2a 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 RB2a groups are joined to form an optionally substituted heterocyclic ring;
• or RB1 and RB2 are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl ring;
• X is —NRx—;
• L2 is —NRL2aC(═O)—, —C(═O)NRL2a—, —S(═O)2NRL2a—, or —NRL2aS(═O)2—, wherein each instance of RL2a is independently hydrogen, optionally substituted C1-6 alkyl, or a nitrogen protecting group;
• each instance of RC 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, —ORC1, —N(RC1)2, and —SRC1, wherein each occurrence of RC1 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 RC1 groups are joined to form an optionally substituted heterocyclic ring;
• n is 0, 1, 2, 3, or 4;
• each instance of RD 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, —ORD1, —N(RD1)2, and —SRD1, wherein each occurrence of RD1 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 RD1 groups are joined to form an optionally substituted heterocyclic ring;
• p is 0, 1, 2, 3, or 4;
• RE is of the formula:
• RE and L2 are para or meta to each other;
• L3 is a bond, —O—, —S—, —NRL3a—, or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b—, —C≡—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein each instance of RL3a is independently hydrogen, optionally substituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b 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 RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• RE1 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, —CH2ORE1a, —CH2N(RE1a)2, —CH2SRE1a, —ORE1a, —N(RE1a)2, and —SRE1a, wherein each occurrence of RE1a 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 RE1a groups are joined to form an optionally substituted heterocyclic ring;
• RE2 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, —CH2ORE2a, —CH2N(RE2a)2, —CH2SRE2a, —ORE2a, —N(RE2a)2, and —SRE2a, wherein each occurrence of RE2a 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 RE2a groups are joined to form an optionally substituted heterocyclic ring;
• RE3 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, —CH2ORE3a, —CH2N(RE3a)2, —CH2SRE3a, —ORE3a, —N(RE3a)2, and —SRE3a, wherein each occurrence of RE3a 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 RE3a groups are joined to form an optionally substituted heterocyclic ring;
• or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• and
• Y is O, S, or NRE5, wherein RE5 is hydrogen, optionally substituted C1-6 alkyl, or a nitrogen protecting group;
• provided that the transcription inhibitor and the kinase inhibitor are not the same.