Reference - Detail
| RRC ID | 86120 |
|---|---|
| Author | Shi Y, Jiang Q, Li L, Zuo Y, Jiang S, Yan T, Zheng C, Zhang S, Yu N, Cao J, Liu Y, Ai Y, Wang Y. |
| Title | Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1. |
| Journal | Blood |
| 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. |
| Volume | 146(17) |
| Pages | 2088-2101 |
| Published | 2025-10-23 |
| DOI | 10.1182/blood.2025028539 |
| PII | 546319 |
| PMID | 40700636 |
| MeSH | Allosteric Regulation / drug effects Animals Antineoplastic Agents* / pharmacokinetics Antineoplastic Agents* / pharmacology Blood-Brain Barrier / metabolism Brain* / drug effects Brain* / metabolism Cell Line, Tumor Cell Proliferation / drug effects Fusion Proteins, bcr-abl* / antagonists & inhibitors Fusion Proteins, bcr-abl* / genetics Fusion Proteins, bcr-abl* / metabolism Humans Imidazoles / pharmacology Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / pathology Mice Protein Kinase Inhibitors* / pharmacokinetics Protein Kinase Inhibitors* / pharmacology Pyridazines / pharmacology Rats Xenograft Model Antitumor Assays |
| IF | 17.794 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 4 |
| Altmetric score changes over past 6months | 1.0 |
| Resource | |
| Human and Animal Cells | Ba/F3(RCB0805) |