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

Abstract

Clinical resistance or intolerance to tyrosine kinase inhibitors (TKIs) 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 developed the gatekeeper mutations or compound mutations. Here, we describe the preclinical profile of TGRX-678, an allosteric inhibitor designed to Specifically Target the ABL1 Myristoyl Pocket (STAMP), with potent anti-proliferative activity against the majority of ATP site mutants of BCR::ABL1 and minimal off-target cytotoxicity. When combined with ponatinib, TGRX-678 synergistically re-sensitizes 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 ABCB1 and ABCG2. It also demonstrates a markedly improved in vivo pharmacokinetic (PK) profile and higher oral bioavailability compared to asciminib. Importantly, TGRX-678 penetrates the blood-brain barrier (BBB) and exhibits in vivo efficacy in a murine CNS blast crisis leukemia model. 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.