Last update 01 Nov 2024

CDK5 x CDK2 x CDK1 x CDK3 x CDK9

Last update 01 Nov 2024

Basic Info

Related Targets

CDK5CDK2CDK1[+2]

Drugs associated with CDK5 x CDK2 x CDK1 x CDK3 x CDK9

NVP-LCQ195

Target

CDK1 x CDK2 x CDK3 x CDK5 x CDK9

Mechanism

CDK1 inhibitors [+4]

Active Org.-

Originator Org.

Astex Therapeutics Ltd.

Active Indication-

Inactive Indication

Multiple Myeloma

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CDK5 x CDK2 x CDK1 x CDK3 x CDK9

100 Translational Medicine associated with CDK5 x CDK2 x CDK1 x CDK3 x CDK9

0 Patents (Medical) associated with CDK5 x CDK2 x CDK1 x CDK3 x CDK9

Literatures (Medical) associated with CDK5 x CDK2 x CDK1 x CDK3 x CDK9

01 Oct 2023·Investigational new drugs

Development of novel palbociclib-based CDK4/6 inhibitors exploring the back pocket behind the gatekeeper.

Article

Author: Li, Lina ; Xue, Xia ; Chen, Fengquan ; Liao, Yongxiang ; Li, Mengzhe ; Luan, Yun ; Wang, Yongjie ; Jiang, Wen

CDK4/6 inhibitors plus endocrine therapy is a standard therapy for HR+/HER2- breast cancer. Herein, using structure-based drug design strategy, a novel series of palbociclib derivatives were designed and synthesized as CDK4/6 inhibitors, among which compound 17m exhibited more potent CDK4/6 inhibitory activity and in vitro antiproliferative activity against the phosphorylated Rb-positive cell line MDA-MB-453 than the approved drug palbociclib. Moreover, compound 17m possessed remarkable CDK4/6 selectivity over other CDK family members including CDK1, CDK2, CDK3, CDK5, CDK7 and CDK9. The potent and selective CDK4/6 inhibitory activity endowed compound 17m with robust G1 cell cycle arrest ability in MDA-MB-453 cells. The intracellular inhibition of CDK4/6 by 17m was confirmed by western blot analysis of the levels of phosphorylated Rb in MDA-MB-453 cells. With respect to the metabolic stability, compound 17m possessed longer half-life (t_1/2) in mouse liver microsome than palbociclib.

01 Feb 2011·British Journal of HaematologyQ2 · MEDICINE

Molecular and cellular effects of multi‐targeted cyclin‐dependent kinase inhibition in myeloma: biological and clinical implications

Q2 · MEDICINE

Article

Author: Jana Jakubikova ; Christoph Lengauer ; Jacob Laubach ; Robert Schlossman ; Hannah M. Jacobs ; Constantine S. Mitsiades ; Douglas W. McMillin ; Leutz Buon ; Patrick Hayden ; Melissa Ooi ; Joseph Negri ; Paul G. Richardson ; Jake Delmore ; Kenneth C. Anderson ; Nikhil C. Munshi

SummaryCell cycle regulators, such as cyclin‐dependent kinases (CDKs), are appealing targets for multiple myeloma (MM) therapy given the increased proliferative rates of tumour cells in advanced versus early stages of MM. We hypothesized that a multi‐targeted CDK inhibitor with a different spectrum of activity compared to existing CDK inhibitors could trigger distinct molecular sequelae with therapeutic implications for MM. We therefore studied the small molecule heterocyclic compound NVP‐LCQ195/AT9311 (LCQ195), which inhibits CDK1, CDK2 and CDK5, as well as CDK3 and CDK9. LCQ195 induced cell cycle arrest and eventual apoptotic cell death of MM cells, even at sub‐μmol/l concentrations, spared non‐malignant cells, and overcame the protection conferred to MM cells by stroma or cytokines of the bone marrow milieu. In MM cells, LCQ195 triggered decreased amplitude of transcriptional signatures associated with oncogenesis, drug resistance and stem cell renewal, including signatures of activation of key transcription factors for MM cells e.g. myc, HIF‐1α, IRF4. Bortezomib‐treated MM patients whose tumours had high baseline expression of genes suppressed by LCQ195 had significantly shorter progression‐free and overall survival than those with low levels of these transcripts in their MM cells. These observations provide insight into the biological relevance of multi‐targeted CDK inhibition in MM.

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