| Autor: |
Jeon JY; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Buelow DR; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Garrison DA; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Niu M; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Eisenmann ED; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Huang KM; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Zavorka Thomas ME; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Weber RH; Division of Pharmaceutics and Pharmacology, College of Pharmacy., Whatcott CJ; Sumitomo Dainippon Pharma Oncology., Warner SL; Sumitomo Dainippon Pharma Oncology., Orwick SJ; Division of Hematology, Department of Internal Medicine, and., Carmichael B; Division of Hematology, Department of Internal Medicine, and., Stahl E; Division of Hematology, Department of Internal Medicine, and., Brinton LT; Division of Hematology, Department of Internal Medicine, and., Lapalombella R; Division of Hematology, Department of Internal Medicine, and.; Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio, USA., Blachly JS; Division of Hematology, Department of Internal Medicine, and.; Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio, USA., Hertlein E; Division of Hematology, Department of Internal Medicine, and.; Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio, USA., Byrd JC; Division of Pharmaceutics and Pharmacology, College of Pharmacy.; Division of Hematology, Department of Internal Medicine, and.; Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio, USA., Bhatnagar B; Division of Hematology, Department of Internal Medicine, and.; Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio, USA., Baker SD; Division of Pharmaceutics and Pharmacology, College of Pharmacy.; Division of Hematology, Department of Internal Medicine, and.; Comprehensive Cancer Center, The Ohio State University (OSU), Columbus, Ohio, USA. |
| Abstrakt: |
Effective treatment for AML is challenging due to the presence of clonal heterogeneity and the evolution of polyclonal drug resistance. Here, we report that TP-0903 has potent activity against protein kinases related to STAT, AKT, and ERK signaling, as well as cell cycle regulators in biochemical and cellular assays. In vitro and in vivo, TP-0903 was active in multiple models of drug-resistant FLT3 mutant AML, including those involving the F691L gatekeeper mutation and bone marrow microenvironment-mediated factors. Furthermore, TP-0903 demonstrated preclinical activity in AML models with FLT3-ITD and common co-occurring mutations in IDH2 and NRAS genes. We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL-PTD, ASXL1, SRSF2, and WT1, which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML. |
