| RRC ID |
86120
|
| 著者 |
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.
|
| タイトル |
Preclinical characterization of TGRX-678, a brain-penetrant allosteric inhibitor of BCR::ABL1.
|
| ジャーナル |
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.
|
| 巻・号 |
146(17)
|
| ページ |
2088-2101
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805) |
