Overcoming BTK inhibitor resistance in B-cell malignancies

Covalent inhibition of Bruton s tyrosine kinaseBTKis a clinically validated mechanism for treating B cell malignancies as illustrated by the FDA approval of ibrutinibIin mantle cell lymphomaMCLinand acalabrutinibAa more kinase selectivend generation covalent inhibitor approved infor second line MCLHowevertheseagents become ineffective in about one third of MCL patients because of primary resistance andto a lesser extentinhibitor induced resistanceWe have created ard generation covalent BTK inhibitorSRXwith more kinase selectivity than A to further decrease side effectsMoreoverSRXwas designed to inhibit potently two additional key cancer targets that are synergistic against BTKPIkinasePI Kand the bromodomain protein BRDWe also demonstrate that blocking these two targets it increases activity towards MCL cell lines and overcomes both primary and inhibitor induced resistance versus I or AThis approach is significant because it will dramatically expand the patient population likely to respond to and benefit from ourrd generation BTK inhibitors beyond the current CLL and MCL populationsA key innovative component of our proposal is our effective utilization of in silico models to design and synthesize SRXthe first in class small molecule chemotype that potently inhibits BTKPI K and BRDin the same cellpreliminary resultsOur demonstratedproof of conceptwith SRXincludesmore kinase selective vsnd generation BTK inhibitor acalabrutiniblow nM potency and inhibition of all three cancer targets in cell based assaysX more potent than I A on resistant MCL cell linesX more tumor growth inhibition in vivo vs I in mouse MCL xenograft modelX less toxic on normal epithelial cells vs combination of three separate inhibitorsBTKi BRD i PI KiThis proposal will further characterize our lead SRXwhile obtaining a back up molecule for Phase II development with a focus on MCLSpecific AimsAimTaskDevelop ard generation BTK inhibitor with improved efficacy against resistant B cell malignanciesApproachEvaluate and characterize SRXfor early ADME and toxAimTaskIdentify SRXback up candidateApproachIn parallel to Aimmodel in silico amembered virtual library of SRXanalogs against BTKsynthesize predicted topBTK inhibitorsobtain their BTK inhibition profiletest them against resistant B cell malignancy cell linesand obtain key ADME parametersAimTaskDemonstrate superiority to IbrutinibIand AcalabrutinibAApproachCompare toxicitynormal B cells epithelial cellsand efficacy of SRXor back upvs I A in mouse tumor models and cellular assays including cysteine to serine resistant cells and intrinsic resistant cell linesThe results of this work will set the stage for a Phase II SBIR focusing on the development of SRXor improved analog through pre IND studies 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 BTK inhibitor that also inhibits two other key cancer targets PI K and BRDto should show great efficacy for patients with B cell malignanciesMoreoverthe proposal is designed to advance a platform technology for the development of other multi targeted small molecule inhibitors of cancer 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