2. Academic Validation
  3. Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML

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

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: wmfayd@163.com.
  • 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: chejx@zju.edu.cn.
  • 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: mying@zju.edu.cn.
  • 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: dongxw@zju.edu.cn.
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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