更新于：2024-11-01

Cyclin dependent kinase 2 degraders(Monte Rosa Therapeutics AG)

更新于：2024-11-01

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

CDK2-based molecular glue degraders - Monte Rosa Therapeutics、Research programme: cyclin dependent kinase 2 degraders - Monte Rosa Therapeutics、cyclin dependent kinase 2 degraders(Monte Rosa Therapeutics AG)

靶点

CDK2

作用机制

CDK2抑制剂(细胞周期蛋白依赖性激酶2抑制剂)

治疗领域

肿瘤内分泌与代谢疾病皮肤和肌肉骨骼疾病+ [1]

在研适应症

乳腺癌卵巢癌

非在研适应症-

原研机构

Monte Rosa Therapeutics AG

在研机构

Monte Rosa Therapeutics AG

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 Cyclin dependent kinase 2 degraders(Monte Rosa Therapeutics AG) 相关的临床结果

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100 项与 Cyclin dependent kinase 2 degraders(Monte Rosa Therapeutics AG) 相关的转化医学

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100 项与 Cyclin dependent kinase 2 degraders(Monte Rosa Therapeutics AG) 相关的专利（医药）

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项与 Cyclin dependent kinase 2 degraders(Monte Rosa Therapeutics AG) 相关的文献（医药）

2023-09-01·Drug development research

Design, synthesis, and biological evaluation of furan-bearing pyrazolo[3,4-b]pyridines as novel inhibitors of CDK2 and P53-MDM2 protein-protein interaction.

Article

作者: Ezzat, Manal Abdel Fattah ; Elewa, Safaa I ; Fouad, Marwa A ; Elmasry, Ghada F ; Abdel-Aziz, Hatem A ; El-Mageed, Menna M A Abd

The novel series of furan-bearing pyrazolo[3,4-b]pyridines were designed as cyclin-dependent kinase 2 (CDK2) inhibitors and as p53-murine double minute 2 (MDM2) inhibitors.The newly synthesized compounds were screened for their antiproliferative activity toward hepatocellular carcinoma (HepG2) and breast cancer (MCF7) cell lines.The most active compounds on both cell lines were addnl. evaluated for their in vitro CDK2 inhibitory activity.Compounds 7b and 12f displayed enhanced activity (half-maximal inhibitory concentration [IC₅₀] = 0.46 and 0.27 μM, resp.) in comparison to the standard roscovitine (IC₅₀ = 1.41 ± 0.03 μM), in addition to, cell cycle arrest at S phase and G1/S transition phase in MCF7 cells treated with both compounds, resp.Moreover, the most active spiro-oxindole derivative against MCF7 cell line, 16a, exhibited enhanced inhibitory activity against p53-MDM2 interaction in vitro (IC₅₀ = 3.09 ± 0.12 μM) compared to nutlin, and increased the levels of both p53 and p21 by nearly fourfold in comparison to the neg. control.Mol. docking studies demonstrated the plausible interaction patterns of the most potent derivatives 17b and 12f in the CDK2 binding pocket and the spiro-oxindole 16a with p53-MDM2 complex, resp.Consequently, the new chemotypes 7b, 12f, and 16a can be presented as promising antitumor hits for further studies and optimization.

2023-09-01·Drug development research

Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives linked morpholine moiety as CDK2 inhibitors

Article

作者: Medrasi, Hanadi Y. ; Abbas, Eman M. H. ; Pashameah, Rami Adel ; Harras, Marwa F. ; Farghaly, Thoraya A. ; Al-Sheikh, Mariam A. ; Masaret, Ghada S. ; Qurban, Jihan

With the aim of developing cyclin-dependent kinase 2 (CDK2) inhibitors with strong antibreast cancer efficacy, new tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives were synthesized. The newly synthesized tri- and tetracyclic derivatives were achieved from the reaction of 4-(4-morpholin-4-yl-phenyl)-1,3,4,5,6,7-hexahydro-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-thione (5) with α-haloketone derivatives as hydrazonyl chlorides, phenacyl bromide derivatives, chloroacetone, and ethyl substituted acetate derivatives. The MCF-7 and MDA-MB-231 breast cancer cell lines were utilized to examine the anticancer properties. Compounds 5 and 8 were shown to be the most effective, with half-maximal inhibitory concentration (IC₅₀ ) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. Mechanistic studies showed that 5 and 8 caused tumor cell death by inducing apoptosis and they also produced cancer arrest in the S phase of the cell cycle. In addition, compounds 5 and 8 showed strong anti-CDK2 action (IC₅₀ = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC₅₀ = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.

2023-02-09·Journal of Medicinal Chemistry1区 · 医学

Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice

1区 · 医学

Article

作者: John, Kristen ; Faber, Erik B. ; Sun, Luxin ; Francis, Rawle ; Schönbrunn, Ernst ; Wang, Nan ; Wong, Henry L. ; Levinson, Nicholas M. ; Hong, Kwon H. ; Yang, An ; Tian, Defeng ; Elsaid, Mazen ; Khalid, Hira ; Georg, Gunda I. ; Burban, David ; Wang, Liming ; Hawkinson, Jon E.

Although cyclin-dependent kinase 2 (CDK2) is a validated target for both cancer and contraception, developing a CDK2 inhibitor with exquisite selectivity has been challenging due to the structural similarity of the ATP-binding site, where most kinase inhibitors bind. We previously discovered an allosteric pocket in CDK2 with the potential to bind a selective compound and then discovered and structurally confirmed an anthranilic acid scaffold that binds this pocket with high affinity. These allosteric inhibitors are selective for CDK2 over structurally similar CDK1 and show contraceptive potential. Herein, we describe the screening and optimization that led to compounds like EF-4-177 with nanomolar affinity for CDK2. EF-4-177 is metabolically stable, orally bioavailable, and significantly disrupts spermatogenesis, demonstrating this series' therapeutic potential. This work details the discovery of the highest affinity allosteric CDK inhibitors reported and shows promise for this series to yield an efficacious and selective allosteric CDK2 inhibitor.

项与 Cyclin dependent kinase 2 degraders(Monte Rosa Therapeutics AG) 相关的新闻（医药）

2024-06-12

·BioSpace

Ensem Therapeutics Announces Achievement of Milestone Following Entry of Small Molecule CDK2 Inhibitor into Clinical Trials for Solid Tumors

ETX-197/BG-68501 is the first clinical-stage compound discovered with ENSEM’s Kinetic Ensemble® Platform WALTHAM, Mass.--(BUSINESS WIRE)-- Ensem Therapeutics, Inc. today announced that its partner BeiGene has dosed the first five patients in its first-in-human Phase 1 trial to evaluate BG-68501, a small molecule cyclin-dependent kinase 2 (CDK2) inhibitor for the treatment of solid tumors. The achievement triggers a milestone payment from BeiGene, which licensed the compound (formerly ETX-197) from ENSEM in November 2023. BG-68501 is the first clinical stage compound to emerge from ENSEM’s Kinetic Ensemble® platform, a suite of novel AI/ML, computational and experimental technologies to uncover cryptic pockets in target proteins for drug discovery. “CDK2 hyperactivity plays a well-recognized role in many cancers but has been an extremely challenging target for drug discovery,” said Shengfang Jin, CEO and Co-Founder of ENSEM. “Through our partner BeiGene, which has a proven track record of innovative clinical development, we have an initial opportunity to test our novel approach to targeting cryptic sites, which are not obvious in static protein structures.” The Phase 1 clinical trial, conducted by BeiGene, is evaluating BG-68501 in advanced or metastatic solid tumors potentially associated with CDK2 dependency, including HR+/HER2- breast cancer, platinum refractory or resistant serous ovarian, fallopian tube, primary peritoneal cancer, small cell lung cancer, and others (NCT06257264). “The complete nonclinical development of ETX-197 by ENSEM, from conceptualization to IND submission in two years, has validated ENSEM’s platform and demonstrated expeditious project execution,” noted Dr. Jin. ENSEM is currently advancing multiple early-stage programs targeting oncogenic drivers, anticipating nomination of two development candidates in 2024. About Ensem Therapeutics ENSEM is a pioneering drug discovery and development company that leverages its unique Kinetic Ensemble® platform to advance innovative small molecule precision medicines for oncology. ENSEM integrates computational, AI deep learning, and cutting-edge experimental methodologies to identify non-obvious binding pockets and accelerate structure-based drug design, with a focus on high-value and difficult-to-drug targets. For more information, please visit , or engage with us on LinkedIn.

临床1期

2023-11-21

·PipelineReview

BeiGene and Ensem Therapeutics Announce Partnership to Advance Differentiated CDK2 Inhibitor

BASEL, Switzerland & BEIJING, China & CAMBRIDGE, MA & WALTHAM, MA, USA I November 21, 2023 I BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, and Ensem Therapeutics, Inc. (ENSEM), a biotechnology company focusing on high-value and difficult-to-drug oncology targets, today announced an agreement for BeiGene to acquire an exclusive global license to an Investigational New Drug (IND) application-ready oral cyclin-dependent kinase 2 (CDK2) inhibitor. “We are committed to developing novel molecules with the potential to transform the therapeutic landscape for cancer patients, and this partnership fits well with our strategic focus on breast cancer as an area with tremendous unmet need for innovative treatment options” “We are committed to developing novel molecules with the potential to transform the therapeutic landscape for cancer patients, and this partnership fits well with our strategic focus on breast cancer as an area with tremendous unmet need for innovative treatment options,” said Lai Wang, Ph.D., Global Head of R&D at BeiGene. “This CDK2 inhibitor from ENSEM complements our internally discovered Phase 1 CDK4 inhibitor, which has the potential to improve upon current CDK4/6 inhibitors in some breast cancer patients, and strengthens our early development pipeline in breast cancer and other solid tumors. We are excited to work with ENSEM to bring this molecule into the clinic in the near future.” Under the terms of the agreement, ENSEM will receive an upfront payment, and will be eligible for additional payments upon the achievement of certain development, regulatory, and commercial milestones, totaling up to $1.33 billion, in addition to tiered royalties. “We are pleased to partner with BeiGene on the development of this differentiated CDK2 inhibitor,” said Shengfang Jin, Ph.D., President and Chief Executive Officer at ENSEM. “We believe BeiGene is the right partner to advance our first IND-ready asset due to their wealth of expertise in bringing innovative cancer therapies to patients globally. This partnership validates the capabilities of ENSEM’s drug discovery and development team and the ability to rapidly advance potential best-in-class or first-in-class molecules utilizing our Kinetic Ensemble ® platform. We look forward to progressing our additional pipeline programs to help patients in need and supporting BeiGene’s important work to take this therapy into clinical trials.” About Ensem Therapeutics ENSEM is a pioneering drug discovery and development company that leverages its unique Kinetic Ensemble® platform to develop innovative small molecule precision medicines for oncology. ENSEM integrates computational and AI deep learning methodologies with advanced experimental techniques to identify non-obvious binding pockets and accelerate structure-based drug design, with a focus on high-value and difficult-to-drug targets. For more information, please visit www.ensemtx.com , or engage with us on LinkedIn . About BeiGene BeiGene is a global biotechnology company that is discovering and developing innovative oncology treatments that are more affordable and accessible to cancer patients worldwide. With a broad portfolio, we are expediting development of our diverse pipeline of novel therapeutics through our internal capabilities and collaborations. We are committed to radically improving access to medicines for far more patients who need them. Our growing global team of more than 10,000 colleagues spans five continents, with administrative offices in Basel, Beijing, and Cambridge, U.S. To learn more about BeiGene, please visit www.beigene.com and follow us on LinkedIn and X (formerly known as Twitter). SOURCE: BeiGene

引进/卖出临床1期

2023-11-21

·EndPoints

BeiGene licenses CDK2 inhibitor from Ensem in potential $1.33B deal

BeiGene has struck a deal with Ensem Therapeutics to license an oral cyclin-dependent kinase 2 (CDK2) inhibitor in exchange for an undisclosed upfront payment and up to $1.33 billion in milestones, the companies announced Tuesday . Ensem will also get tiered royalties for handing over the exclusive global license to the drug, which the companies said is “Investigational New Drug (IND) application-ready” and Ensem’s most advanced candidate. While they didn’t name the program in the press release, Ensem’s website identifies the BeiGene-partnered program as ETX-197. You’ll get access to free articles each month, plus you can customize what newsletters get delivered to your inbox each week, including breaking news.