Targeting Mcl-1 to Enhance DNA Replication Stress Sensitivity for Cancer Therapy

Abstract

This disclosure relates to inhibitors of Mcl-1 stimulated homologous recombination (HR) DNA repair and uses for treating cancer. In certain embodiments, this disclosure relates to methods of treating cancer comprising administering an inhibitor of Mcl-1 in combination with other anti-cancer agents, e.g., that induce DNA replication stress. In certain embodiments, this disclosure relates to methods of treating cancer comprising administering compounds disclosed herein in combination with hydroxyurea, olaparib, or combinations thereof.

1 . A pharmaceutical composition comprising a compound_2-(2-chlorophenyl)-3-(((5-ethoxy-6-oxocyclohexa-2,4-dien-1-ylidene)methyl)amino)quinazolin-4(3H)-one or salt thereof and a pharmaceutically acceptable excipient. 
     
     
         2 . The pharmaceutical composition of  claim 1 , where the pharmaceutical composition further comprises hydroxyurea or olaparib. 
     
     
         3 . The pharmaceutical composition of  claim 1 , where the pharmaceutical composition further comprises a chemotherapy agent. 
     
     
         4 . The pharmaceutical composition of  claim 3 , where the chemotherapy agent is selected from bevacizumab, trastuzumab, imatinib, lenalidomide, pemetrexed, bortezomib, cetuximab, leuprorelin, abiraterone, alemtuzumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, avelumab, cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, cisplatin, capecitabine, folinic acid, and oxaliplatin. 
     
     
         5 . The pharmaceutical composition of  claim 1  in the form of a tablet or capsule. 
     
     
         6 . The pharmaceutical composition of  claim 1  in the form of a tablet or capsule comprising an enteric coating. 
     
     
         7 . The pharmaceutical composition of  claim 1  in the form of a capsule comprising beads, particles or granules. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is a binder, lubricant, surfactant, preservative, or antioxidant. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is a pH buffering agent. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is sodium chloride. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from cellulose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from polyethylene glycol, glycerol behenate, ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, and polyglyceryl-4-oleate. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from starch, dry starch, hydrolyzed starch, and pregelatinized starch. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from a sugar, powdered sugar, dextrose, lactose, sucrose, mannitol, sorbitol, fructose, mannitol, and glucose. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from acrylic acid and methacrylic acid copolymers. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from magnesium stearate, calcium stearate, and stearic acid. 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from dicalcium phosphate dihydrate, calcium sulfate, kaolin, silicone dioxide, titanium oxide, and magnesium aluminum silicate. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from sodium dodecylbenzene sulfonate, sodium bis-(2-ethylthioxyl)-sulfosuccinate, and sodium lauryl sulfate. 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable excipient is selected from benzalkonium chloride, benzethonium chloride, cetrimonium bromide, and stearyl dimethylbenzyl ammonium chloride. 
     
     
         20 . The compound 2-(2-chlorophenyl)-3-(((5-ethoxy-6-oxocyclohexa-2,4-dien-1-ylidene)methyl)amino)quinazolin-4(3H)-one or salt thereof packaged in a box, blister, vial, bottle, or ampoule containing product information or instructions for use.