Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Yanxia Shi1, Qian Jiang2,3, Linxin Li1
1Department of Biological and Translational Research, Shenzhen TargetRx, Inc, Shenzhen, China.
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.
Insights
A new drug, TGRX-678, shows promise for treating chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) that resist current therapies. This allosteric inhibitor effectively targets BCR::ABL1 mutations, including those in the central nervous system (CNS).
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Clinical resistance and intolerance to tyrosine kinase inhibitors (TKIs) present significant challenges in treating chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL), particularly with central nervous system (CNS) relapse.
- Limited therapeutic options exist for patients with advanced BCR::ABL1 mutations, including gatekeeper and compound mutations, which confer resistance to existing treatments.
Purpose of the Study:
- To evaluate the preclinical profile and therapeutic potential of TGRX-678, a novel allosteric inhibitor targeting the ABL1 myristoyl pocket (STAMP).
- To assess TGRX-678's efficacy, selectivity, pharmacokinetic properties, and ability to overcome resistance mechanisms in BCR::ABL1-driven leukemias, including CNS involvement.
Main Methods:
- Preclinical assessment of TGRX-678's anti-proliferative activity against various BCR::ABL1 mutants, including compound mutations and T315M.
- Evaluation of TGRX-678's synergistic effects when combined with ponatinib.
- Assessment of TGRX-678's cell permeability, drug efflux transporter substrate status (ABCB1, ABCG2), in vivo pharmacokinetics (PK), oral bioavailability, and blood-brain barrier (BBB) penetration.
- Testing TGRX-678's efficacy in a murine model of CNS blast crisis leukemia.
Main Results:
- TGRX-678 demonstrated potent anti-proliferative activity against most ATP-site mutants of BCR::ABL1 with minimal off-target cytotoxicity.
- Combination therapy with ponatinib synergistically re-sensitized highly resistant compound mutants and T315M to growth inhibition at clinically achievable concentrations.
- TGRX-678 exhibited favorable cell permeability, was not a substrate for ABCB1/ABCG2 efflux transporters, and showed improved PK profile and oral bioavailability compared to asciminib.
- Importantly, TGRX-678 effectively penetrated the BBB and showed in vivo efficacy in a murine CNS leukemia model.
Conclusions:
- TGRX-678 is a novel, highly selective, and potent allosteric inhibitor of BCR::ABL1 with unique pharmacologic properties.
- Its ability to overcome resistance mutations and penetrate the CNS makes TGRX-678 a promising candidate for treating relapsed or refractory CML and Ph+ ALL, including cases with CNS involvement.
