Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML

  • Eur J Med Chem. 2024 May 31:275:116539. doi: 10.1016/j.ejmech.2024.116539.
Mingfei Wu  1 ,  Wei Wang  2 ,  Xinfei Mao  2 ,  Yiquan Wu  3 ,  Yuyuan Jin  4 ,  Tao Liu  3 ,  Yan Lu  5 ,  Haibin Dai  5 ,  Shenxin Zeng  4 ,  Wenhai Huang  4 ,  Yuwei Wang  6 ,  Xiaojun Yao  7 ,  Jinxin Che  8 ,  Meidan Ying  9 ,  Xiaowu Dong  10
Affiliations
  • 1. Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
  • 2. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences; Zhejiang University, Cancer Center; Zhejiang University School of Medicine Children'sHospital, Division of Hematology-Oncology, Hangzhou, 310058, PR China.
  • 3. Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 4. Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310058, PR China.
  • 5. Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, PR China.
  • 6. College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, PR China.
  • 7. Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macau, 999078, PR China.
  • 8. Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
  • 9. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences; Zhejiang University, Cancer Center; Zhejiang University School of Medicine Children'sHospital, Division of Hematology-Oncology, Hangzhou, 310058, PR China. Electronic address: [email protected].
  • 10. Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, PR China. Electronic address: [email protected].
PMID: 38878515 DOI: 10.1016/j.ejmech.2024.116539
Abstract

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3, featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC50 value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML.

Keywords
AML; CDKs; Differentiation therapy; FLT3; PROTACs; Proliferation inhibition.
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