Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1

Abstract Clinical resistance or intolerance to tyrosine kinase inhibitors remains challenging for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) with central nervous system (CNS) relapse. Therapeutic options are currently limited for patients who develop the gatekeeper mutations or compound mutations. Herein we describe the preclinical profile of TGRX-678, an allosteric, specifically targeting the ABL myristoyl pocket (STAMP) inhibitor, with potent antiproliferative activity against most adenosine triphosphate (ATP) site mutants of BCR::ABL1 and minimal off-target cytotoxicity. When combined with ponatinib, TGRX-678 synergistically resensitizes the highly resistant compound mutants and T315M to growth inhibition at clinically achievable concentrations. TGRX-678 exhibits relatively high cell permeability and is not a substrate of drug efflux transporters, namely ATP-binding cassette B1 (ABCB1) and ABCG2. It also demonstrates a markedly improved in vivo pharmacokinetic profile and higher oral bioavailability compared with asciminib. Importantly, TGRX-678 penetrates the blood-brain barrier and exhibits in vivo efficacy in a murine model of CNS blast crisis leukemia. Collectively, these findings suggest that TGRX-678 is a novel BCR::ABL1 allosteric inhibitor with high selectivity, potency, and unique pharmacologic features, which has the potential to treat relapse or refractory CML and Ph+ ALL, even with CNS involvement.