CDK2

撰文丨王聪编辑丨王多鱼排版丨水成文致癌突变在正常人体组织中普遍存在，人体内有着数万亿个细胞，致癌突变在这些正常细胞中突变存在，然而，这些致癌突变通常并不会引起癌症，这也导致了癌症实际上并不常见。同样，在小鼠嵌合体中，携带致癌突变的细胞能为成年组织提供正常细胞，而不会引发癌症。那些通过正常发育而避开癌症的细胞谱系与少数最终罹患癌症的细胞谱系有何不同，目前尚不清楚。2025 年 4 月 30 日，四川大学华西医院陈大年教授作为第一作者，联合多伦多大学西奈山医院 Rod Bremner 教授团队在国际顶尖学术期刊 Nature 上发表了题为：Cell cycle duration determines oncogenic transformation capacity 的研究论文。该研究发现，细胞分裂周期在易患癌的细胞类型中更快，证实了细胞周期快是新发现的癌症易感性预测指标。肿瘤具有典型的癌症特征；因此，研究团队寻找了区分易患癌症的细胞谱系和抗性细胞谱系的特征。在这项最新研究中，研究团队发现，总细胞周期持续时间（Tc）可预测多种肿瘤类型的转化易感性。易患癌症的 Rb 和 p107 缺陷的视网膜（Rb 又称 Rb1， p107 又称 Rbl1）在细胞凋亡、衰老、免疫监视、血管生成、DNA 修复、极性和增殖等方面存在缺陷。干扰 SKP2-p27-CDK2/CDK1 轴能够阻断癌症，且不影响这些特征。因此，癌症的形成不仅仅取决于其标志性特征的存在。值得注意的是，研究团队测试的每一个肿瘤抑制突变都增加了 Tc，而视网膜母细胞瘤细胞起源细胞的 Tc 是耐药谱系的一半。Tc 还区分了 Rb-/- 垂体癌的起源细胞。在肺部，Rb 和 p53 的缺失会将神经内分泌细胞转化，而 KrasG12D 或 BrafV600E 突变则会将肺泡Ⅱ型细胞转化。最短的 Tc 始终能确定细胞起源，无论突变发生的时间如何。因此，相对 Tc 是一个标志，它在多种情况下区分了易患癌和抗癌的细胞谱系，解释了突变细胞如何在不引发细胞凋亡、衰老或免疫监视的情况下逃脱转化。总的来说，该研究发现了易患癌细胞的共同特征——它们的细胞分裂周期比抗肿瘤细胞更快。Nature 期刊同期配发了题为：The cell-division cycle is faster in cell types prone to forming cancer 的新闻与评论文章，该文章指出，易患癌的细胞相比抗癌细胞的分裂周期更快，细胞周期快可作为一种癌症易感性预测的新指标。论文链接：https://www.nature.com/articles/s41586-025-08935-x设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群 微信加群 为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

Fast Track designation highlights potential of INX-315 to address unmet need for patients with recurrent advanced/metastatic cancerRESEARCH TRIANGLE PARK, N.C., April 29, 2025 (GLOBE NEWSWIRE) -- Incyclix Bio, LLC, a next-generation cell cycle control company developing INX-315, a novel, potent and selective CDK2 inhibitor for the treatment of advanced and resistant cancer, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for INX-315 for the treatment of CCNE1-amplified platinum-resistant/refractory ovarian cancer. “The FDA’s decision to grant Fast Track designation for INX-315 reflects the best-in-class potential of our CDK2 inhibitor, the strength of our preclinical and early clinical data and the urgency to address significant unmet need in patients with CCNE1-amplified platinum-resistant/refractory ovarian cancer,” said Patrick Roberts, PharmD, PhD, Chief Executive Officer and Co-Founder of Incyclix Bio. “We look forward to working closely with the FDA to advance the clinical development of INX-315 to bring it to patients as soon as possible.” The FDA grants Fast Track designation to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Treatments that receive Fast Track designation may benefit from more frequent interactions with the FDA throughout development. In addition, the Fast Track program allows for eligibility for Accelerated Approval and Priority Review, if relevant criteria are met. Amplification of CCNE (cyclin E1 and E2) occurs in a broad range of solid tumors and in a significant subset of patients with high-grade serous ovarian cancer (HGSOC). CCNE1-amplification is also correlated with resistance to platinum-based chemotherapy, creating an area of high unmet need in patients with the most common type of ovarian cancer. INX-315 is a novel, potent and selective CDK2 inhibitor that is being evaluated in INX-315-01, an ongoing first-in-human Phase 1/2 clinical trial to evaluate its safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity in patients with recurrent advanced/metastatic cancer. INX-315 is an investigational drug product and has not been approved by the FDA. More information on the trial can be found at clinicaltrials.gov (NCT05735080). About Incyclix Bio Incyclix Bio is a next-generation cell cycle control company advancing precision treatments that target the aberrant proliferation driving many cancers. The company’s lead compound, INX-315, is a potent and selective cyclin-dependent kinase 2 (CDK2) inhibitor in clinical development. Incyclix Bio is a scientific leader in understanding cyclin-dependent kinases (CDKs) and their role in the cell cycle as attractive therapeutic targets across many tumor types, including ovarian, breast and lung cancers. Headquartered in Research Triangle Park, NC, Incyclix Bio is founded by pioneers in CDK inhibitor discovery, research and development. For more information, visit incyclixbio.com. Media Contact:Tony Plohoros908-591-2839tplohoros@6degreespr.com

-PLX-61639, a selective, oral SMARCA2 degrader, demonstrated sustained PD response and single-agent efficacy in SMARCA4 mutant tumors; program is advancing through IND-enabling studies- -PLX-4545, a selective IKZF2 molecular glue degrader, completely degraded IKZF2 across a range of well-tolerated doses in Phase 1, resulting in a shift from Treg to an effector-like T cell phenotype- -Preclinical data was presented on its CDK2 selective molecular glue degrader, which exhibited superior selectivity over inhibitor-based approaches; program is targeting CCNE1 amplified cancers- SAN DIEGO, April 28, 2025 /PRNewswire/ -- Plexium, Inc. (Plexium), a leading next-generation targeted protein degradation company, announced today multiple presentations with the Company's selective monovalent degrader programs for SMARCA2, IKZF2 and CDK2 at the 2025 American Association for Cancer Research (AACR) Annual Meeting, taking place April 25-30, 2025, in Chicago, IL. "These data highlight the clinical and preclinical progress we've made across our portfolio, including the use of a novel E3 ligase DCAF16, in our SMARCA2 program—an industry first that reinforces the differentiated potential of our monovalent degrader platform," said Jorge F. DiMartino, MD, PhD, Chief Medical Officer at Plexium. "We are also excited to share initial clinical data from PLX-4545, which demonstrated clinical proof of mechanism and intended pharmacological immunophenotypic effects." Oral Presentation Details: Title: "Discovery and characterization of novel, potent and selective CDK2 molecular glue degrader against CCNE1-amplified tumors" Session: MS.ET09.01 – Degraders and Glues Abstract Number: 6375 Date and Time: April 29, 2:55 PM – 3:10 PM Presenting Author: Leenus Martin, PhD Title: "PLX-4545, a selective IKZF2 degrader, reprograms suppressive Tregs leading to tumor growth inhibition and combination benefit with immune checkpoint therapy" Session: MS.ET09.01 – Degraders and Glues Abstract Number: 6380 Date and Time: April 29, 4:10 PM – 4:25 PM Presenting Author: Peggy Thompson, PhD Poster Presentation Highlights: Title: "Mechanistic characterization of selective monovalent direct degraders of SMARCA2″ Session: PO.ET09.04 – Degraders and Glues 1 Abstract Number: 404 Section: 18 Date and Time: April 27, 2025, 2:00 PM – 5:00 PM Presenting Author: Julia Toth, PhD Plexium's SMARCA2 degraders function by bromodomain binding and covalent modification A CRISPR knockout screen identified DCAF16 as being required for PLX-61639 mediated SMARCA2 degradation MOA studies demonstrate PLX-61639-mediated SMARCA2:DCAF16 protein interactions and the requirement of covalent binding to a specific DCAF16 cysteine to support a stable ternary complex and subsequent SMARCA2 degradation Title: "Preclinical characterization of PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader" Session: PO.ET09.10 – Degraders and Glues 2 Abstract Number: 1653 Section: 18 Date and Time: April 28, 2025, 9:00 AM – 12:00 PM Presenting Author: Gregory Parker, PhD Plexium has designed PLX-61639, a potent and selective direct degrader of SMARCA2, and nominated it as a development candidate Daily oral dosing of PLX-61639 results in deep and sustained SMARCA2 degradation, eliciting robust tumor growth inhibition and regression in SM4mut CDX and PDX models, no tumor growth inhibition is observed in a control SM4wt CDX model PLX-61639 is currently advancing through IND-enabling studies Title: "A first in human trial of PLX-4545, a molecular glue degrader of IKZF2, in healthy volunteers, shows pharmacologic modulation of Tregs at well-tolerated doses" Session Title: PO.CT01.02. First-in-Human Phase I Clinical Trials 2 Abstract Number: CT150 Section: 48 Date and Time: April 29, 2025, 9:00 AM – 12 PM Presenting Author: Jorge DiMartino, MD, PhD PLX-4545 an oral, CRBN molecular glue degrader of IKZF2, a lineage-defining transcription factor for Tregs was tested in healthy adult volunteers With repeated daily dosing for 14 days, all dose levels achieved complete degradation of IKZF2 in PBMCs by Day 2 leading to conversion of Tregs into effector-like T cells and an increase in activated T effector cells TEAEs were mostly Grade 1 or 2 (mild or moderate) in severity and no Dose Limiting Toxicities were encountered. All AEs were reversible with discontinuation of dosing The AACR 2025 posters will be made available on the Plexium website. About Plexium Inc. Plexium is the premier, next-generation Targeted Protein Degradation (TPD) company seeking to discover a wide range of monovalent degraders that address the limitations of first-generation heterobifunctional degraders. The company is powered by its proprietary AI-integrated ultra-high-throughput phenotypic drug discovery platform technologies that have enabled the identification of novel small molecules that induce E3 ligase mediated selective degradation of target proteins. From molecular glues to direct degraders, Plexium is advancing a pipeline of novel monovalent targeted protein degraders for the treatment of cancer, neurodegeneration, and other diseases. For more information, visit and engage with us on LinkedIn. Plexium Investor and Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Plexium WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED