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

Eur J Med Chem. 2024 Sep 5:275:116539. doi: 10.1016/j.ejmech.2024.116539. Epub 2024 May 31.

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.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinases* / antagonists & inhibitors
  • Cyclin-Dependent Kinases* / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Molecular Structure
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Proteolysis Targeting Chimera* / chemistry
  • Proteolysis Targeting Chimera* / pharmacology
  • Proteolysis Targeting Chimera* / therapeutic use
  • Proteolysis*
  • Structure-Activity Relationship
  • fms-Like Tyrosine Kinase 3* / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3* / metabolism

Substances

  • Antineoplastic Agents
  • Cyclin-Dependent Kinases
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Protein Kinase Inhibitors
  • Proteolysis Targeting Chimera