2. Academic Validation
  3. Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia

  • J Med Chem. 2021 Jun 10;64(11):7434-7452. doi: 10.1021/acs.jmedchem.1c00082.
Dongfeng Zhang 1,  Peng Li 1,  Yongxin Gao 1,  Yaoyao Song 2,  Yaqin Zhu 2,  Hong Su 2,  Beibei Yang 1,  Li Li 1,  Gang Li 1,  Ningbo Gong 3,  Yang Lu 3,  Huanjie Shao 2,  Chunrong Yu 4,  Haihong Huang 1
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.
  • 2 College of Life Sciences, Shaanxi Normal University, 620 Xi Chang An Street, Xi'an 710119, P. R. China.
  • 3 Beijing Key Laboratory of Polymorphic Drugs, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.
  • 4 Taizhou Astar BioTechnology Co. Ltd, Kou Tai Road, Taizhou 225300, P. R. China.
PMID: 34011155 DOI: 10.1021/acs.jmedchem.1c00082
Abstract

Bcr-Abl kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against Bcr-Abl mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and Bcr-Abl and Bcr-AblT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring Bcr-AblT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I Bcr-Abl mutation.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z