Last update 01 Nov 2024

CDK5 x CDK2 x CDK1 x CDK9 x CDK7

Last update 01 Nov 2024

Basic Info

Related Targets

CDK5CDK2CDK1[+2]

Drugs associated with CDK5 x CDK2 x CDK1 x CDK9 x CDK7

BS-194

Target

CDK1 x CDK2 x CDK5 x CDK7 x CDK9

Mechanism

CDK1 inhibitors [+4]

Active Org.

Imperial College London

Originator Org.

Imperial College London

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CDK5 x CDK2 x CDK1 x CDK9 x CDK7

100 Translational Medicine associated with CDK5 x CDK2 x CDK1 x CDK9 x CDK7

0 Patents (Medical) associated with CDK5 x CDK2 x CDK1 x CDK9 x CDK7

Literatures (Medical) associated with CDK5 x CDK2 x CDK1 x CDK9 x CDK7

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.

10 Aug 2020·Angewandte Chemie International EditionQ1 · CHEMISTRY

Development of CDK2 and CDK5 Dual Degrader TMX‐2172

Q1 · CHEMISTRY

Article

Author: Teng, Mingxing ; Victor, Chiara ; Fischer, Eric S. ; Sorger, Peter K. ; Zhang, Tinghu ; Mills, Caitlin E. ; Jiang, Jie ; Hatcher, John M. ; Kwiatkowski, Nicholas P. ; Donovan, Katherine A. ; He, Zhixiang ; Gray, Nathanael S.

AbstractCyclin‐dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of cancer. Development of CDK2 inhibitors has been extremely challenging as its ATP‐binding site shares high similarity with CDK1, a related kinase whose inhibition causes toxic effects. Here, we report the development of TMX‐2172, a heterobifunctional CDK2 degrader with degradation selectivity for CDK2 and CDK5 over not only CDK1, but transcriptional CDKs (CDK7 and CDK9) and cell cycle CDKs (CDK4 and CDK6) as well. In addition, we demonstrate that antiproliferative activity in ovarian cancer cells (OVCAR8) depends on CDK2 degradation and correlates with high expression of cyclin E1 (CCNE1), which functions as a regulatory subunit of CDK2. Collectively, our work provides evidence that TMX‐2172 represents a lead for further development and that CDK2 degradation is a potentially valuable therapeutic strategy in ovarian and other cancers that overexpress CCNE1.

01 Jun 2018·Molecular Cancer TherapeuticsQ2 · MEDICINE

ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

Q2 · MEDICINE

Article

Author: Coombes, R. Charles ; Barrett, Anthony G. M. ; Periyasamy, Manikandan ; Slafer, Brian W. ; Patel, Hetal ; Bondke, Alexander ; Fuchter, Matthew J. ; Ali, Simak ; Buluwela, Laki ; Aboagye, Eric O. ; Kroll, Sebastian H. B. ; Barbazanges, Marion ; Starkey, Richard ; Ottaviani, Silvia ; Harrod, Alison ; Sava, Georgina P.

AbstractRecent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40 nmol/L; IC50 values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. Mol Cancer Ther; 17(6); 1156–66. ©2018 AACR.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis