PPP2R1A

前言 AIDD Pro 根据国内外各大网站以及人工智能药物设计主流新闻网站及公众号，从 AIDD会议、AIDD招聘，重大科研进展、行业动态、最新报告发布等角度，分析挖掘了每周人工智能辅助药物设计领域所发生的、对领域技术发展产生重大推动作用的事件，旨在帮助 AIDD领域研究人员和业内人士及时追踪最新科研动态、洞察前沿热点。如果您觉得符合以上要求的内容我们有遗漏或者更好建议，欢迎后台留言。 科研进展2024年10月12日【药物设计】Cryst. Growth Des. | 溶剂介导的鞣花酸·吩嗪共晶体中分子填料对生物活性增强和合理药物设计的作用2024年10月11日【迁移学习】J. Chem. Inf. Model. | 通过迁移学习机制提高新型HIV-1蛋白酶抑制剂耐药的预测疗效2024年10月10日【机器学习】J. Chem. Theory Comput. | 结合分子动力学和机器学习算法预测激酶配体的功能谱2024年10月10日【深度学习】J. Chem. Theory Comput. | 使用深度学习生成用于路径发现的蛋白质结构2024年10月10日【SARS-CoV-2】J. Chem. Inf. Model. | 基于分子机制的新型小分子抑制剂对耐药SARS-CoV-2 Mpro变体的发现2024年10月9日【蛋白激酶】J. Med. Chem. | 靶向蛋白激酶，膜相关酪氨酸/苏氨酸1 （PKMYT1）用于精确癌症治疗：从发现到临床试验 具体信息，请滑动下方文字 1.【药物设计】 鞣花酸（elagic acid， EA）是一种富含多种天然植物的具有生物活性的多酚，已广泛应用于多种药理体系中。本研究调查了EA与常见药物中间体形成的共晶，对其原子水平的生物学性能产生了至关重要的见解。在不同溶剂下合成了三种新型EA·吩那嗪共晶(共晶1:EA·吩那嗪；共晶2:EA·非那嗪·2MeOH；共晶3:EA·非那嗪·2H2O)。此外，用单晶x射线衍射对其结构进行了表征。无晶格溶剂的共晶1和含有晶格水的共晶3表现出了有趣的EA-EA和非那嗪-非那嗪π -π堆叠相互作用。相反，含甲醇的共晶2可以说明配体间EA/吩那嗪π -π堆叠相互作用。因此，共晶2显示出更宽的吸收范围和更负的氧化电位，表明增强的功能性能。理论计算表明，共晶2的优越性质是由于其最低的未占据分子轨道，特别是苯那嗪的p−π*反键轨道的能量较低，这是由于π -π相互作用的结果。总之，配体间相互作用的存在是增强共晶生物活性的关键因素，增强的程度取决于特定的包装模式。这种结构-性质关系允许对药物分子中观察到的多态性有深刻的理解。 链接网址：https://pubs.acs.org/doi/10.1021/acs.cgd.4c00805 DOI：https://doi.org/10.1021/acs.cgd.4c00805 2.【迁移学习】 人类免疫缺陷病毒由于其快速突变和对抗逆转录病毒药物的耐药性机制的发展，对全球健康构成了重大挑战。最近的研究表明，机器学习（ML）和深度学习（DL）模型在预测特定fda批准的抑制剂的耐药谱方面表现出色。然而，推广ML和DL模型，不仅从分离物中学习，而且从抑制剂表征中学习，对HIV-1感染仍然具有挑战性。我们提出了一种新的药物分离-折叠变化（DIF）模型框架，旨在直接从蛋白质序列和抑制剂表示预测耐药评分。通过现实验证机制分析了各种ML和DL模型、抑制剂表示和蛋白质表示。为了提高DIF模型的分子学习能力，我们采用迁移学习方法，对4855个HIV-1蛋白酶抑制剂（pi）数据集进行了图神经网络（GNN）模型的活性预测。通过对内部和外部基因型-表型数据集执行各种现实验证策略，我们统计地表明，抑制剂的学习表征提高了基于dif的ML和DL模型的预测能力。对于未见的外部pi，我们实现了0.802的精度，0.874的AUROC和0.727的r。通过将基于DIF的模型与由隔离折叠变化（IF）结构组成的零模型进行比较，可以观察到DIF模型明显受益于分子表示。各种测试策略和统计测试的综合结果证实了DIF模型在存在分离物的情况下测试新型pi耐药的有效性。 链接网址：https://pubs.acs.org/doi/10.1021/acs.jcim.4c01037 DOI：https://doi.org/10.1021/acs.jcim.4c01037 3.【机器学习】 通过设计小分子来调节蛋白质的功能为化学生物学和药物化学提供了新的机会。虽然传统上开发的药物是通过占据活性位点来阻断酶的活性，但现在越来越多的策略旨在以变构方式控制蛋白质功能，允许通过调节其功能基础的构象群来调节目标的激活或失活。在发现新的活性导联的背景下，对新配体的功能影响产生假设将是非常有用的。由于变构调节剂（抑制剂/激活剂）的发现和设计仍然是一个具有挑战性的目标，并且经常是偶然的目标，因此开发一种快速而稳健的方法来预测新配体的功能特征将大大加快候选配体的选择。在这里，我们提出了不同的机器学习（ML）分类器来区分潜在的正构和变构粘合剂。我们的方法将配体的化学指纹信息与描述符相结合，这些描述符概括了配体对蛋白质功能运动的影响。后者来源于靶蛋白与正构或变构配体复合物的分子动力学（MD）模拟。在这个框架中，我们训练和测试了不同的ML结构，这些结构最初是在细胞周期蛋白依赖性激酶（CDKs）的正构配体和变构配体的分类上进行了探讨。结果表明，不同的机器学习方法可以成功地划分变构效应和正构效应（尽管程度不同）。接下来，我们用fda批准的CDK药物（未包括在原始数据集中）以及靶向其他激酶的配体进一步测试这些模型，以测试这些模型在其开发的领域之外的适用性范围。总体而言，研究结果表明，利用基于化学物理的蛋白质-配体动态串导信息丰富训练数据集，可以显著扩大小分子作用模式预测和分类方法的覆盖范围和适用性。 链接网址：https://pubs.acs.org/doi/10.1021/acs.jctc.4c01097 DOI：https://doi.org/10.1021/acs.jctc.4c01097 4.【深度学习】 在分子水平上解决生物现象的复杂细节，从根本上受到可以通过实验探测的长度和时间尺度的限制。分子动力学（MD）在各种尺度上的模拟是强大的工具，经常被用来提供有价值的超越实验分辨率的生物学见解。然而，虽然在所需的空间分辨率下观察长期稳定的结构（例如蛋白质）相对简单，但模拟这些状态之间更有趣的罕见转变通常需要的时间比在当今可用的最大超级计算机上所能做到的要长几个数量级。这一挑战的一个常见方面是途径发现，即科学现象的开始和结束状态是已知的或可以近似的，但两者之间的机制细节是未知的。在这里，我们提出了一种基于表示学习的解决方案，该解决方案在抽象表示空间中使用插值和外推来合成潜在的过渡状态，并使用MD模拟自动验证。合成过渡状态的新模拟随后被纳入表征学习，导致目标路径采样的迭代框架。我们的方法是通过使用粗粒MD模拟恢复RAS-RAF蛋白结构域（CRD）从无膜到与膜相互作用的转变来证明的。 链接网址：https://pubs.acs.org/doi/10.1021/acs.jctc.4c00816 DOI：https://doi.org/10.1021/acs.jctc.4c00816 5.【SARS-CoV-2】 在靶向SARS-CoV-2 Mpro的拟肽共价药物nirmatrelvir的选择性压力下，Mpro在体外获得了多种耐药突变。在这些突变中，L50F和E166V以及L50F和E166V的组合尤其具有代表性，对有效治疗COVID-19构成了相当大的障碍。我们之前的研究发现NMI-001和NMI-002是针对SARS-CoV-2 Mpro的新型非肽抑制剂，具有不同于nirmatrelvir的独特支架和结合模式。鉴于这些发现，我们提出了一种药物设计策略，旨在快速识别可以对抗突变诱导的耐药性的抑制剂。首先，采用分子动力学（MD）模拟研究NMI-001和NMI-002与3种耐药突变体（Mpro_L50F、Mpro_E166V和Mpro_L50F+E166V）的结合机制。然后，我们进行了两个阶段的高通量虚拟筛选。在第一阶段，NMI-001作为模板在15,742,661个化合物的文库中执行基于支架跳跃的相似性搜索。在第二阶段，通过分子对接和MD模拟对968个与NMI-001相似的化合物进行了评估。鉴定了六种可能对至少一种突变体有效的化合物，并获得了五种化合物进行体外测定。最后，发现化合物Z1557501297 （NMI-003）对E166V （IC50 = 27.81±2.65 μM）和L50F+E166V （IC50 = 8.78±0.74 μM）具有抑制作用。在原子水平上进一步阐明了NMI-003-Mpro_E166V和NMI-003-Mpro_L50F+E166V的结合模式。综上所述，本文报道的NMI-003是首个具有抗E166V和L50F+E166V活性的化合物，为设计治疗耐药SARS-CoV-2的新型抗病毒药物提供了良好的起点。 链接网址：https://pubs.acs.org/doi/10.1021/acs.jcim.4c01206 DOI：https://doi.org/10.1021/acs.jcim.4c01206 6.【蛋白激酶】 蛋白激酶膜相关酪氨酸/苏氨酸1 （PKMYT1）是WEE家族中一个被忽视的成员，负责调节细胞周期转变，由于其与CCNE1（周期蛋白E1）扩增建立了合成致死关系，最近成为精确癌症治疗的一个引人注目的治疗靶点。自同类首个选择性PKMYT1抑制剂RP-6306于2021年进入临床试验以来，随着抑制剂专利数量的增加和对其他基因改变（如KRAS/p53突变、FBXW7突变和PPP2R1A突变）的探索，该领域再次引起人们的兴趣。这一观点首次总结了迄今为止文献和专利申请中报道的PKMYT1的结构、功能和抑制剂。化合物的描述重点是它们的设计和优化过程，结构特征和生物活性，旨在促进进一步的药物发现工作，以PKMYT1为潜在的精确治疗。 链接网址：https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01619 DOI：https://doi.org/10.1021/acs.jmedchem.4c01619 上下滚动查看更多 药企动态2024年10月12日【诺华】诺华「布西珠单抗」新适应症国内报上市2024年10月11日【恒瑞医药】恒瑞医药EZH2抑制剂国内申报上市2024年10月10日【罗氏】PFS翻倍！FDA批准罗氏PI3Kα抑制剂2024年10月10日【沃森生物】沃森生物：双价HPV疫苗在印度尼西亚获批上市2024年10月9日【百奥泰】1.1亿美元！百奥泰「乌司奴单抗」出海欧洲药企2024年10月9日【拜耳】拜耳first-in-class疗法上市申请获FDA受理各动态具体信息，请滑动下方文字 1.【诺华】 10 月 12 日，CDE 官网显示，诺华的布西珠单抗 (Brolucizumab) 新适应症在国内报上市，推测适应症为湿性年龄相关性黄斑变性。 链接网址请戳我 2.【恒瑞医药】 10月11日，CDE官网显示，恒瑞医药的EZH2抑制剂SHR2554片申报上市。这是首个申报上市的国产EZH2抑制剂。 链接网址请戳我 3.【罗氏】 10月10日，FDA批准罗氏旗下基因泰克（Genentech）公司开发的口服小分子疗法Inavolisib (Itovebi)联合CDK4/6抑制剂palbociclib和氟维司群fulvestrant ,用于肿瘤携带PIK3CA突变、内分泌耐药、pik3ca突变、激素受体(HR)阳性、人表皮生长因子受体2 (HER2)阴性、局部晚期或转移性乳腺癌成年患者。 链接网址请戳我 4.【沃森生物】 10月10日，沃森生物发布公告，子公司玉溪泽润的双价人乳头瘤病毒疫苗近日获得印度尼西亚食品与药品管理局的产品上市许可证，预灌封和西林瓶两个品规均获批。该疫苗主要用于预防由高危型HPV16、18型引起的相关疾病，如宫颈癌等。 链接网址请戳我 5.【百奥泰】10月9日，百奥泰发布公告，公司与GedeonRichterPlc.（“吉瑞医药”）就BAT2206（乌司奴单抗）注射液签署授权许可及生产、供货和商业化协议，将公司的BAT2206（乌司奴单抗）注射液在欧盟、英国、瑞士、澳大利亚以及其他部分欧洲国家市场的独占的产品商业化权益有偿许可给吉瑞医药。 链接网址请戳我 6.【拜耳】 10月9日，拜耳宣布美国FDA已受理双重NK-1/NK-3受体拮抗剂Elinzanetant（依林奈坦）的新药上市申请（NDA），适应症为更年期相关的中度至重度血管舒缩症状（VMS），即更年期潮热。 链接网址请戳我 上下滚动查看更多 会议信息 2024年10月18-20日 天津市生物医药行业协会举办中国(天津)国际生物医药产业博览会 2024年10月24-25日 E药学苑举办ChemCon 2024第四届小分子药物创新开发论坛2025年1月9-10日 举办ICGT第八届细胞与基因治疗深度聚焦峰 各会议具体详情和参会方式，请滑动下方文字 中国(天津)国际生物医药产业博览会 主办方：天津市生物医药行业协会 会议时间：2024年10月18-20日 会议地点：天津 会议主旨：为贯彻落实“十四五”规划和 2035 年远景目标，加快建设高质量生物医药体系，加快推动我国生物医药产业创新升级，加强生物医药产业的交流与合作，提升企业品牌和认知度，博览会立足天津辐射全国，发挥京津冀协同发展区域优势定位于“国际化、品牌化、专业化”，推动生物医药行业高质量发展中的重要作用，加速优质项目市场布局，助力中国生物医药事业的发展，助推中国迈入生物医药强国行列。 链接网址请戳我 ChemCon 2024第四届小分子药物创新开发论坛 主办方：E药学苑 会议时间：2024年10月24-25日 会议地点：南京 会议主旨：作为目前药物研发领域的主流，小分子药物具有许多优势和挑战。为推动研发和产业化的发展，促进行业内的学术交流与合作，邀请近百名知名专家学者分享他们在小分子创新药、改良型新药等领域的科研成果以及独到见解。 链接网址请戳我 ICGT第八届细胞与基因治疗深度聚焦峰 会议时间：2025年1月9-10日 会议地点：上海 会议主旨：共同探讨CGT产业链上中下游的关键环节，覆盖细胞免疫、眼科、罕见病和CMC热点议题，直面行业痛点，破解发展难点，共迎CGT产业的黄金十年。 链接网址请戳我 上下滚动查看更多 版权信息 本文内容均由小编收集于公开的各个网络平台，发布的目的仅为了方便大家一站式了解AIDD行业信息，并未对发布源头进行真实性验证。如您发现相关信息有任何版权侵扰或者信息错误，请及时联系AIDD Pro（请添加微信号sixiali_fox59）进行删改处理。 原创内容未经授权，禁止转载至其他平台。有问题可发邮件至sixiali@stonewise.cn 关注我，更多资讯早知道↓↓↓

Data presented at AACR’s Ovarian Cancer Research Symposium confirm that ovarian and endometrial cancers with CCNE1 amplifications, FBXW7 or PP2R1A mutations carry poor prognosis Significant survival disparities were identified in patients harboring lunresertib- and camonsertib-sensitizing biomarkers, including CCNE1 amplifications or mutations in FBXW7 or PPP2R1A CAMBRIDGE, Mass. & MONTREAL --(BUSINESS WIRE)--Sep. 23, 2024-- Repare Therapeutics Inc. (“Repare” or the “Company”) (Nasdaq: RPTX), a leading clinical-stage precision oncology company, presented new data on Friday highlighting the impact of alterations in FBXW7, PPP2R1A and CCNE1 in patients with metastatic ovarian and endometrial cancers based on an analysis in approximately 2,000 patients from Cancer Genome Atlas Research Network and Memorial Sloan Kettering’s Metastatic Events and Tropisms. The poster presentation was shared at the American Association of Cancer Research’s (AACR) 15th Annual Ovarian Cancer Research Symposium in Seattle , underscores inherent chemotherapy resistance and the lack of treatment options for metastatic gynecologic cancer patients with these biomarkers. “Patients with recurrent ovarian and endometrial cancers are already at a disadvantage when it comes to treatment options,” said Maria Koehler , MD, PhD, Executive Vice President and Chief Medical Officer of Repare. “These new data highlight the urgent need for innovative therapeutic approaches to address the specifically poor prognosis associated with FBXW7, PPP2R1A and CCNE1 alterations treated with standard of care-based chemotherapy. We look forward to reporting data from our MYTHIC dose expansion trial evaluating lunresertib in combination with camonsertib in patients with ovarian and endometrial cancers with these biomarkers in the fourth quarter of 2024.” Repare Therapeutics’ Phase 1 MYTHIC clinical trial (NCT04855656) is studying the combination of lunresertib, a first-in-class oral small molecule PKMYT1 inhibitor, and camonsertib, a potential best-in-class oral small molecule ATR inhibitor, in patients harboring lunresertib-sensitizing biomarkers (Lunre BM), including CCNE1 amplifications or mutations in FBXW7 or PPP2R1A. While CCNE1 amplifications occur in approximately 30% of platinum-resistant ovarian cancers,1-2 and are well established as a poor prognostic indicator in ovarian cancer,3-6 little is known about other Lunre BM in ovarian and endometrial cancers. Ovarian Cancer: The presence of Lunre BM (alterations in CCNE1, PPP2R1A, or FBXW7) in ovarian cancer patients (n=1,029) is linked to a substantially lower survival rate compared to those without these biomarkers, underscoring their prognostic significance: Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 26 months (95% CI, 18-38), compared to 36 months (95% CI, 30-43) for patients without these biomarkers (Lunre BM-; HR = 1.46 [95% CI, 1.14-1.87], p=0.003), a 28% decrease in mOS Endometrial Cancer: Endometrial cancer patients (n=895) with biomarkers CCNE1, PPP2R1A, and FBXW7 demonstrate poorer survival outcomes, which are influenced by their association with high-risk histologies and genetic alterations: Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 30 months (95% CI, 24-38), compared to 41 months (95% CI, 31-60) for patients without these biomarkers (Lunre BM-; HR = 1.29 [95% CI, 1.03-1.60], p=0.024), a 27% decrease in mOS The presence of these biomarkers also correlates with high-risk histologies (uterine carcinosarcoma and uterine serous carcinoma) and p53 mutant genotypes, well known for adverse prognosis About Repare Therapeutics Inc. Repare Therapeutics is a leading clinical-stage precision oncology company enabled by its proprietary synthetic lethality approach to the discovery and development of novel therapeutics. The Company utilizes its genome-wide, CRISPR-enabled SNIPRx® platform to systematically discover and develop highly targeted cancer therapies focused on genomic instability, including DNA damage repair. The Company’s pipeline includes lunresertib (also known as RP-6306 ), a PKMYT1 inhibitor currently in Phase 1/2 clinical development; camonsertib (also known as RP-3500 ), a potential leading ATR inhibitor currently in Phase 1/2 clinical development; RP-1664 , a Phase 1 PLK4 inhibitor; RP-3467 , a preclinical Polθ ATPase inhibitor program; as well as additional, undisclosed preclinical programs. For more information, please visit reparerx.com and follow @Reparerx on X (formerly Twitter) and LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 and securities laws in Canada . All statements in this press release other than statements of historical facts are “forward-looking statements. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding: the impact of alterations in FBXW7, PPP2R1A and CCNE1 in patients with metastatic ovarian and endometrial cancers; the design, objectives, initiation, timing, progress and results of current and future clinical trials of the Company’s product candidates, including the timing of data from the expansion of its Phase 1 MYTHIC trial evaluating lunresertib alone and in combination with camonsertib; the potential of lunresertib in combination with camonsertib in patients harboring lunresertib-sensitizing biomarkers and the tolerability, efficacy and clinical progress of the Company’s product candidates. These forward-looking statements are based on the Company’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause the Company’s clinical development programs, future results or performance to differ materially from those expressed or implied by the forward-looking statements. Many factors may cause differences between current expectations and actual results, including: the potential that success in preclinical testing and earlier clinical trials does not ensure that later clinical trials will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of a product candidate; the impacts of macroeconomic conditions, including the conflict in Ukraine and the conflict in the Middle East , heightened inflation and uncertain credit and financial markets, on the Company’s business, clinical trials and financial position; unexpected safety or efficacy data observed during preclinical studies or clinical trials; clinical trial site activation or enrollment rates that are lower than expected; the Company’s ability to realize the benefits of its collaboration and license agreements; changes in expected or existing competition; changes in the regulatory environment; the uncertainties and timing of the regulatory approval process; and unexpected litigation or other disputes. Other factors that may cause the Company’s actual results to differ from those expressed or implied in the forward-looking statements in this press release are identified in the section titled "Risk Factors" in the Company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024 filed with the Securities and Exchange Commission (“SEC”) and the Québec Autorité des Marchés Financiers ("AMF") on August 6, 2024 . The Company expressly disclaims any obligation to update any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. For more information, please visit reparerx.com and follow Repare on X (formerly Twitter) at @RepareRx and on LinkedIn at https://www.linkedin.com/company/repare-therapeutics/. 1. Cancer Genome Atlas Research Network. Nature. 2011;474(7353):609–615 2. Smith P, et al. Nat Commun . 2023;14(1):4387 3. Chan AM, et al. J Pathol Clin Res. 2020;6(4):252–262 4. Kang E-Y, et al. Cancer. 2023;129(5):697–713 5. Nakayama N, et al. Cancer. 2010;116(11):2621–2634 6. Stronach EA, et al. Mol Cancer Res. 2018;16(7):1103–1111. View source version on businesswire.com: https://www.businesswire.com/news/home/20240923948019/en/ Investor Relations & Media Contact: Robin Garner Vice President and Head of Investor Relations Repare Therapeutics Inc. investor@reparerx.com Source: Repare Therapeutics Inc.

Focuses Company’s resources on its deep clinical oncology pipeline Positioned to advance four clinical programs through multiple upcoming milestones CAMBRIDGE, Mass. & MONTREAL --(BUSINESS WIRE)--Aug. 28, 2024-- Repare Therapeutics Inc. (“Repare” or the “Company”) (Nasdaq: RPTX), a leading clinical-stage precision oncology company, today announced the strategic reprioritization of its research and development activities to focus its efforts on the advancement of its portfolio of clinical-stage oncology programs. With multiple upcoming clinical milestones and potential near-term registration-enabling studies, the Company is streamlining its operations to focus on the advancement of its lunresertib, camonsertib, RP-1664 and RP-3467 programs while materially reducing the scale of its preclinical research and discovery activities. “We acknowledge today the extraordinary contributions and productivity of our discovery team, who have enabled the development of our deep, innovative clinical portfolio. In our mission to rapidly develop new, practice-changing therapies, we will more fully dedicate our resources to our most promising and advanced precision oncology programs to maximize value for patients and for our shareholders,” said Lloyd M. Segal , President and Chief Executive Officer of Repare. “We remain on track to report data from our MYTHIC dose expansion trial evaluating lunresertib in combination with camonsertib in patients with ovarian and endometrial cancers in the fourth quarter of 2024, with the potential to begin a registrational trial in 2025.” As part of this strategic refocus, Repare plans to reduce its overall workforce by approximately 25%, with a majority of the headcount reductions from the Company’s preclinical group. Repare expects total non-recurring cash payments of approximately $1.5 million to $2.0 million in the third quarter of 2024 associated with the workforce reduction, and expects to generate annual savings of approximately $15.0 million that will extend its cash runway into the second half of 2026, while aggressively pursuing the further development of its clinical portfolio. “I want to thank all of our impacted Repare colleagues who have contributed to the pioneering research and innovation, some for more than seven years, to significantly advance Repare in its mission to deliver novel medicines for patients in need,” continued Segal. Clinical Programs and Upcoming Milestones: Lunresertib (RP-6306): First-in-class, oral small molecule inhibitor of PKMYT1 Repare expects to report data from the ongoing MYTHIC dose expansion clinical trial of lunresertib and camonsertib at the recommended Phase 2 dose (RP2D) in patients with platinum-resistant ovarian and endometrial cancers harboring CCNE1 amplification or FBXW7 or PPP2R1A mutations in the fourth quarter of 2024, with the potential to begin a registrational trial in 2025. Repare is evaluating lunresertib in combination with Debio 0123, a highly selective, brain-penetrant, clinical WEE1 inhibitor, in Module 4 of the ongoing MYTHIC trial in patients with advanced solid tumors harboring CCNE1 amplification or FBXW7 or PPP2R1A deleterious alterations. Repare expects to report initial data from Module 4 of the MYTHIC trial in 2025. Repare also recently reported positive data from the MINOTAUR trial of lunresertib and FOLFIRI showing promising efficacy and duration of therapy in the heavily pretreated population with tumors that harbor CCNE1 amplification and FBXW7 mutation alterations that warrant further development. Camonsertib (RP-3500): Potential best-in-class oral small molecule inhibitor of ATR Repare is evaluating camonsertib as a monotherapy in the ongoing non-small cell lung cancer (NSCLC) expansion of the Phase 2 TRESR clinical trial. Camonsertib has demonstrated a promising signal of prolonged progression free survival in patients with ATM-mutated NSCLC in the TRESR trial. Repare expects to report initial data from the TRESR trial in 2025. RP-1664: First-in-class, highly selective, oral inhibitor of PLK4 Repare is evaluating RP-1664 as a monotherapy in the Phase 1 LIONS clinical trial in adult and adolescent patients with TRIM37-high solid tumors. After evaluating safety in the LIONS trial, the Company expects to rapidly advance RP-1664 into a Phase 1/2 trial in pediatric patients with high risk, recurrent neuroblastoma, where the patients have a high prevalence of TRIM37-altered tumors. RP-3467: Potential best-in-class Polθ ATPase inhibitor Repare expects to initiate a Phase 1 dose-finding clinical trial of RP-3467 in the fourth quarter of 2024. About Repare Therapeutics, Inc. Repare Therapeutics is a leading clinical-stage precision oncology company enabled by its proprietary synthetic lethality approach to the discovery and development of novel therapeutics. The Company utilizes its genome-wide, CRISPR-enabled SNIPRx® platform to systematically discover and develop highly targeted cancer therapies focused on genomic instability, including DNA damage repair. The Company’s pipeline includes lunresertib (also known as RP-6306 ), a PKMYT1 inhibitor currently in Phase 1/2 clinical development; camonsertib (also known as RP-3500 ), a potential leading ATR inhibitor currently in Phase 1/2 clinical development; RP-1664 , a Phase 1 PLK4 inhibitor; RP-3467 , a preclinical Polθ ATPase inhibitor program; as well as additional, undisclosed preclinical programs. For more information, please visit reparerx.com and follow @Reparerx on X (formerly Twitter) and LinkedIn. SNIPRx® is a registered trademark of Repare Therapeutics Inc. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 and securities laws in Canada . All statements in this press release other than statements of historical facts are “forward-looking statements. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding: the Company’s plans for restructuring its workforce and the expected impact of such action, including with respect to anticipated cost savings; the Company’s anticipated cash runway; the design, objectives, initiation, timing, progress and results of current and future preclinical studies and clinical trials of the Company’s product candidates, including its Phase 1 MYTHIC trial evaluating lunresertib alone and in combination with camonsertib, its Phase 1 MINOTAUR trial evaluating lunresertib in combination with FOLFIRI, Module 4 of its Phase 1/1b MYTHIC trial, its Phase 1/1b trial of Debio 0123 and lunresertib in partnership with Debiopharm , its Phase 2 TRESR trial of camonsertib in patients with ATMm, its Phase 1 LIONS trial of RP-1664 , its Phase 1 trial of RP-3467 ; its planned expansion of development of lunresertib plus camonsertib combination; its plans to advance RP-1664 into a Phase 1/2 trial in pediatric patients with high risk, recurrent neuroblastoma; a potential registrational trial in 2025; the tolerability, efficacy and clinical progress of camonsertib, lunresertib, RP-1664 and RP-3467 ; the potential of RP-3467 as a best-in-class Polθ ATPase inhibitor; and the potential synergies of Debio 0123 in combination with lunresertib, lunresertib in combination with camonsertib and lunresertib in combination with FOLFIRI. These forward-looking statements are based on the Company’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause the Company’s clinical development programs, future results or performance to differ materially from those expressed or implied by the forward-looking statements. Many factors may cause differences between current expectations and actual results, including: the potential that success in preclinical testing and earlier clinical trials does not ensure that later clinical trials will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of a product candidate; the impacts of macroeconomic conditions, including the conflict in Ukraine and the conflict in the Middle East , heightened inflation and uncertain credit and financial markets, on the Company’s business, clinical trials and financial position; unexpected safety or efficacy data observed during preclinical studies or clinical trials; clinical trial site activation or enrollment rates that are lower than expected; the Company’s ability to realize the benefits of its collaboration and license agreements; changes in expected or existing competition; changes in the regulatory environment; the uncertainties and timing of the regulatory approval process; and unexpected litigation or other disputes. Other factors that may cause the Company’s actual results to differ from those expressed or implied in the forward-looking statements in this press release are identified in the section titled "Risk Factors" in the Company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024 filed with the Securities and Exchange Commission (“SEC”) and the Québec Autorité des Marchés Financiers ("AMF") on August 6, 2024 . The Company expressly disclaims any obligation to update any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. For more information, please visit reparerx.com and follow Repare on X (formerly Twitter) at @RepareRx and on LinkedIn at https://www.linkedin.com/company/repare-therapeutics/. View source version on businesswire.com: https://www.businesswire.com/news/home/20240828317585/en/ Investor Relations & Media Contact: Robin Garner Vice President and Head of Investor Relations Repare Therapeutics Inc. investor@reparerx.com Source: Repare Therapeutics Inc.