Discovery of novel and orally bioavailable CDK 4/6 inhibitors with high kinome selectivity, low toxicity and long-acting stability for the treatment of multiple myeloma

  • Eur J Med Chem. 2022 Jan 15;228:114024. doi: 10.1016/j.ejmech.2021.114024.
Kai Yuan  1 ,  Wenbin Kuang  1 ,  Weijiao Chen  1 ,  Minghui Ji  1 ,  Wenjian Min  1 ,  Yasheng Zhu  1 ,  Yi Hou  1 ,  Xiao Wang  1 ,  Jiaxing Li  1 ,  Liping Wang  1 ,  Peng Yang  2
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2. State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 34875521 DOI: 10.1016/j.ejmech.2021.114024
Abstract

Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD50 > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.

Keywords
Cyclin-dependent kinases 4/6; Multiple myeloma; Safety properties; Selectivity.
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