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

Kai Yuan; Wenbin Kuang; Weijiao Chen; Minghui Ji; Wenjian Min; Yasheng Zhu; Yi Hou; Xiao Wang; Jiaxing Li; Liping Wang; Peng Yang

doi:10.1016/j.ejmech.2021.114024

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. Epub 2021 Nov 29.

Authors

Kai Yuan¹, Wenbin Kuang¹, Weijiao Chen¹, Minghui Ji¹, Wenjian Min¹, Yasheng Zhu¹, Yi Hou¹, Xiao Wang¹, Jiaxing Li¹, Liping Wang¹, Peng Yang²

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: pengyang@cpu.edu.cn.

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 (t_1/2 > 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.

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Biological Availability
Cell Proliferation / drug effects
Cells, Cultured
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Multiple Myeloma / drug therapy*
Multiple Myeloma / metabolism
Multiple Myeloma / pathology
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
CDK4 protein, human
CDK6 protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6