CDK1

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

Phase 2 registration-intent trial enrolling Part 2a dose confirmation arms Topline data from DENALI Part 2 anticipated by year end 2026 with the potential to support an accelerated approval, subject to FDA feedback SAN DIEGO, April 28, 2025 (GLOBE NEWSWIRE) -- Zentalis® Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company developing a potentially first-in-class and best-in-class WEE1 inhibitor for patients with ovarian cancer and other tumor types, today announced that the first patient has been dosed in Part 2 of the Phase 2 DENALI clinical trial (NCT05128825) of azenosertib in patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC). As previously disclosed, the Company aligned with the U.S. Food and Drug Administration (FDA) on the design of DENALI Part 2, which allows for seamless enrollment in the two parts of the trial: Part 2a is designed to confirm the primary dose-of-interest with a target enrollment of approximately 30 patients at each of two dose levels: 400mg QD 5:2 and 300mg QD 5:2 (intermittent daily dosing on a five days on, two days off dosing schedule).Part 2b is designed to enroll approximately 70 additional patients at the selected dose, which will be informed by the Part 2a results, subject to FDA feedback. The Company expects to disclose topline data from DENALI Part 2 by year end 2026 and if successful, this trial has the potential to support an accelerated approval, subject to FDA review. “Dosing the first patient in Part 2 of the DENALI study is an important milestone for Zentalis as we continue the clinical development of azenosertib,” said Ingmar Bruns, M.D., Chief Medical Officer of Zentalis. “We are proud that azenosertib is one step closer to our goal of addressing a tremendous unmet need. We are grateful to our patients and their families for participating in this trial, which has the potential to result in a treatment option for thousands of women diagnosed with Cyclin E1+ PROC.” Previously disclosed clinical data from Part 1b of the DENALI study showed clinically meaningful results in patients with Cyclin E1+ PROC. As of the January 13, 2025 data cutoff, patients who were response-evaluable (n=43) had an objective response rate (ORR) of 34.9% and a median duration of response (mDOR) of 6.3 months. The mDOR is subject to change as there were patients with ongoing responses as of the cutoff date. The data also established Cyclin E1 protein overexpression, regardless of CCNE1 gene amplification, as a sensitive and specific predictive biomarker that can be used to identify patients who could potentially derive benefit from azenosertib. Zentalis estimates that about half of PROC patients overexpress Cyclin E1 protein based on its proprietary immunohistochemistry cutoff. About Azenosertib Azenosertib is a novel, selective, and orally bioavailable inhibitor of WEE1 currently being evaluated as a monotherapy and combination clinical studies in ovarian cancer and additional tumor types. WEE1 acts as a master regulator of the G1-S and G2-M cell cycle checkpoints, through negative regulation of both CDK1 and CDK2, to prevent replication of cells with damaged DNA. By inhibiting WEE1, azenosertib enables cell cycle progression, despite high levels of DNA damage, thereby resulting in the accumulation of DNA damage and leading to mitotic catastrophe and cancer cell death. About Zentalis Pharmaceuticals Zentalis® Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing azenosertib (ZN-c3), a potentially first-in-class and best-in-class WEE1 inhibitor for patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC). Azenosertib is being evaluated as a monotherapy and in combination across multiple tumor types in clinical trials and has broad franchise potential. In clinical trials, azenosertib has been well tolerated and has demonstrated anti-tumor activity as a single agent across multiple tumor types. The Company is also leveraging its extensive experience and capabilities to translate its science to advance research on additional areas of opportunity for azenosertib outside PROC. Zentalis has operations in San Diego. For more information, please visit www.zentalis.com. Follow Zentalis on X/Twitter at @ZentalisP and on LinkedIn at www.linkedin.com/company/zentalis-pharmaceuticals Forward-Looking Statements This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, as amended. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, but not limited to, statements regarding the potential of azenosertib, including the potential for azenosertib to become a treatment option for women with Cyclin E1+ PROC, our goal for azenosertib to address a tremendous unmet need; our anticipated milestones and the timing thereof, including the timing of clinical data disclosures; the potential to advance research on additional areas of opportunity for azenosertib outside PROC; the potential for azenosertib to be first-in-class and best-in-class; the potential for Cyclin E1 to serve as a sensitive and predictive biomarker that can be used to identify patients who could potentially derive benefit from azenosertib; our estimate of how many PROC patients overexpress Cyclin E1 based on our proprietary immunohistochemistry cutoff; and our planned clinical development strategy and regulatory strategy for azenosertib and the timing thereof, including plans for registration-intent studies and the potential for DENALI Part 2 to support an accelerated approval. The terms “anticipated,” “can,” “could,” “estimate,” “expect,” “intent,” “opportunity,” “potential,” and “will” and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our limited operating history, which may make it difficult to evaluate our current business and predict our future success and viability; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; our plans, including the costs thereof, of development of companion diagnostics; our substantial dependence on the success of azenosertib; the outcome of preclinical testing and early trials may not be predictive of the success of later clinical trials; failure to identify additional product candidates and develop or commercialize marketable products; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process or ongoing regulatory obligations; failure to obtain U.S. or international marketing approval; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties; effects of significant competition; the possibility of system failures or security breaches; risks relating to intellectual property; our ability to attract, retain and motivate qualified personnel, and risks relating to management transitions; significant costs as a result of operating as a public company; and the other important factors discussed under the caption “Risk Factors” in our most recently filed periodic report on Form 10-K or 10-Q and subsequent filings with the U.S. Securities and Exchange Commission (SEC) and our other filings with the SEC. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. ZENTALIS® and its associated logo are trademarks of Zentalis and/or its affiliates. All website addresses and other links in this press release are for information only and are not intended to be an active link or to incorporate any website or other information into this press release. Contact: Haibo Wang - Chief Business OfficerRon Moldaver - Investor Relationsir@zentalis.com

Evariste will be attending the 2025 edition of the AACR Annual Meeting held in Chicago, IL from April 25-30. The company will be presenting a poster detailing the latest progress on EVT-0003023, a potentially best-in-class inhibitor of PKMYT1. Section 21, McCormick Place Convention Center, Chicago, IL | April 28, 9:00 AM - 12:00 PM Authors: Daniel Miller, Alfie Brennan, Jan Lanz, Oliver Vipond, Noah Harrison, James Aaronson, Anna Hercot. Evariste Ltd, London, United Kingdom Title: Discovery and preclinical profiling of a novel PKMYT1 inhibitor, EVT-0003023, with high efficacy in late-stage, post-treatment non-small cell lung cancer models Abstract: Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) is a negative regulator of CDK1 activity and has been identified as a putative synthetic lethal target in cancers which up-regulate cyclin E (CCNE1) or harbor mutations in genes such as FBXW7. We used our internal Frobenius platform to identify highly potent and differentiated inhibitors of PKMYT1 with exceptional selectivity over key off targets, including the Raf family and WEE1. Machine learning-driven optimization delivered a preclinical candidate compound, EVT-0003023, with best-in-class selectivity and a significantly improved pharmacokinetic profile in relevant animal models, and in vivo efficacy in CCNE1-high and FBXW7-mutated xenograft models.Compounds from this series were used to validate a differentiated biomarker for sensitivity to PKMYT1 inhibition in cellular and PDX-derived models, expanding the patient population treatable with PKMYT1 inhibitors into non-small cell lung cancer. Using clinical data, we demonstrated that this biomarker is significantly up-regulated in patients who have progressed on existing standard-of-care treatment, and demonstrated exceptional monotherapy activity for EVT-0003023 in PDX models reflecting this patient population, as well as tumor regression when combined with low doses of chemotherapy. ‍