Discovery of novel CDK4/6-PI3K-BRD4 inhibitor SRX3177 for augmented anti-cancer activity

Three CDKinhibitors were recently approved to treat breast cancerBrCAin combination regimentsDespite significant clinical activitytreatment of BrCA patients with these combinations does not result in a durable responseHencethere is an unmet medical need to develop targeted therapeutic agents which will augment the activity of CDKinhibitors in BrCA and other CDKcyclin D Myc dependent malignanciesA recent report demonstrated that PIkinasePI Kinhibition is critical to maintain CDKsensitivity of tumor cellsHenceour central hypothesis to be tested in this proposal is that combined triple inhibition of CDKPI K and BRDwith one small moleculeSRXwill be more efficacious and less toxic than combining three separate inhibitorsAn innovative component of our proposal is that we have developed in silico guiding models to design and then synthesized SRXthe first small molecule inhibitory chemotype that potently inhibits these three important targetsCDKPIK and BRDsimultaneously in the same cellpreliminary resultsWe have demonstratedproof of conceptthat SRXinhibits all three targets at nM potencyinhibits all three targets in cell based assaysdisplaysfold greater efficacy in cell based assays for ICdeterminationdisplaysfold less toxicity in normal cellsand most importantlydemonstrates efficacy but lacks detectable toxicity in vivo as compared to the high mortality rate observed in mice treated withseparate drugs of equal potencye gPalbociclibCDKBKMPI Kand JQBRDThe significance of our proposal lies in our capacity to provide an optimizable promising single anticancer agent which will potently inhibit CDKCyclin D and Myc via multiple orthogonal signaling mechanisms and inhibit survival signaling by blocking the PI K pathwayThis proposal will evaluate this approach by achieving the following aims setting the stage for phase II efforts to optimize the expected triple inhibitory lead compound sto a clinical candidateAimTaskDevelop a potent CDKinhibitor with inhibitory properties against PI K and BRDApproachIn silico design and modeling ofchemotypes to selectSRXanalogsAimTaskCharacterize thenew compoundsApproachDetermine their CDKBRDand PI K inhibition profiles and ADME propertiesAimTaskDemonstrate triple inhibitor is superior to use of three separate inhibitors in vivoApproachCompare toxicity and efficacy of triple inhibitors versus individual CDKPI KBRDinhibitory conditions in vitro and in vivoThe significance of this research is it will greatly expand the efficacy of CDKinhibition against cyclin D Myc dependent malignant diseasesThis innovative approach attacks cancer blocking three distinctcancer driving orthogonal mechanisms with a single compound with greater safety in vivo challenging the one drug one target dogma Project Narrative The planned research is relevant to public health because data we and others have acquired shows that our proposed development of a potent novel CDKPIkinase BRDtrivalent inhibitor to target cancer with dependency on CDKand PI KMoreoverthe proposal is designed to produce a platform technology for the development of dual or triple valent small molecule inhibitors of PI K combined with inhibitors of other targetsthereby having a broad impact on public healthThus the proposed research which will involve a close collaboration between academia and industry is relevant to the part of the NIH s mission that pertains to the development of new therapeutics able to reduce the burden of human disability via improved treatment of adult and childhood cancer