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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 (LD 50 > 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.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Titel:	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.
Autor/in / Beteiligte Person:	Yuan, K ; Kuang, W ; Chen, W ; Ji, M ; Min, W ; Zhu, Y ; Hou, Y ; Wang, X ; Li, J ; Wang, L ; Yang, P
Zeitschrift:	European journal of medicinal chemistry, Jg. 228 (2022-01-15), S. 114024
Veröffentlichung:	Paris : Editions Scientifiques Elsevier ; <i>Original Publication</i>: Paris, S.E.C.T. [etc.], 2022
Medientyp:	academicJournal
ISSN:	1768-3254 (electronic)
DOI:	10.1016/j.ejmech.2021.114024
Schlagwort:	Administration, Oral Animals Antineoplastic Agents administration & dosage Antineoplastic Agents chemistry Apoptosis drug effects Biological Availability Cell Proliferation drug effects Cells, Cultured Cyclin-Dependent Kinase 4 metabolism Cyclin-Dependent Kinase 6 metabolism Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Humans Mice Mice, Inbred BALB C Mice, Nude Molecular Structure 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 Structure-Activity Relationship Antineoplastic Agents pharmacology Cyclin-Dependent Kinase 4 antagonists & inhibitors Cyclin-Dependent Kinase 6 antagonists & inhibitors Drug Discovery Multiple Myeloma drug therapy Protein Kinase Inhibitors pharmacology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Eur J Med Chem] 2022 Jan 15; Vol. 228, pp. 114024. <i>Date of Electronic Publication: </i>2021 Nov 29. MeSH Terms: Drug Discovery* ; Antineoplastic Agents / pharmacology ; Cyclin-Dependent Kinase 4 / antagonists & inhibitors ; Cyclin-Dependent Kinase 6 / antagonists & inhibitors ; Multiple Myeloma / drug therapy ; Protein Kinase Inhibitors / *pharmacology ; Administration, Oral ; Animals ; Antineoplastic Agents / administration & dosage ; Antineoplastic Agents / chemistry ; Apoptosis / drug effects ; Biological Availability ; Cell Proliferation / drug effects ; Cells, Cultured ; Cyclin-Dependent Kinase 4 / metabolism ; Cyclin-Dependent Kinase 6 / metabolism ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Structure ; 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 ; Structure-Activity Relationship Contributed Indexing: Keywords: Cyclin-dependent kinases 4/6; Multiple myeloma; Safety properties; Selectivity Substance Nomenclature: 0 (Antineoplastic Agents) ; 0 (Protein Kinase Inhibitors) ; EC 2.7.11.22 (CDK4 protein, human) ; EC 2.7.11.22 (CDK6 protein, human) ; EC 2.7.11.22 (Cyclin-Dependent Kinase 4) ; EC 2.7.11.22 (Cyclin-Dependent Kinase 6) Entry Date(s): Date Created: 20211207 Date Completed: 20220126 Latest Revision: 20220126 Update Code: 20231215

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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.