Repare Therapeutics, Inc.

Repare’s chemogenomic discovery platform leverages CRISPR-enabled technology. Credit: Prostock-studio/Shutterstock. Repare Therapeutics has entered an out-licensing agreement with Canadian biotechnology firm DCx Biotherapeutics for discovery platforms and intellectual property (IP). Repare will obtain $4m in upfront and near-term payments from DCx, along with a 10% common equity position. This includes certain dilution protection rights. Repare is also qualified for potential upcoming payments related to out-licensing, commercial and clinical milestones, and low-single-digit tiered sales royalties for DCx’s specific product development. 20 of Repare’s preclinical research employees will be retained by DCx, which will also acquire lease rights to specific laboratory facilities in Montreal, Canada, and equipment. Repare has secured the right to appoint a nominee to DCx’s board of directors. The out-licensed platforms from Repare are the SNIPRx platform, which is validated clinically, early discovery-stage platforms SNIPRx-surf and STEP², and other IP. GlobalData Strategic Intelligence US Tariffs are shifting - will you react or anticipate? Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis. By GlobalData Learn more about Strategic Intelligence Repare Therapeutics CEO, chief financial officer and president Steve Forte stated: “We have taken careful steps to evaluate all aspects of our business to ensure continued value generation, and this out-licensing agreement with DCx for our discovery platforms enables us to further focus on our clinical portfolio and drive cost reductions while maintaining an economic interest in the platform technologies we have developed. “We look forward to reporting initial data from our two ongoing Phase I clinical trials in the second half of 2025, and continue to evaluate partnering and strategic alternatives across our portfolio assets.” The SNIPRx-surf platform is designed to detect cell surface targets in tumours or cancer models, utilising gene expression, protein features and a machine learning algorithm. Repare’s SNIPRx platform has been instrumental in developing targeted therapies for genomic instability and DNA damage repair. A chemogenomic discovery platform, STEP 2 , leverages clustered regularly interspaced short palindromic repeats (CRISPR)-enabled genetic screens with small molecule inhibitors to pinpoint genetic lesions sensitive to these inhibitors. The company’s clinical pipeline encompasses RP-3467, RP-1664 and lunresertib. DCx Biotherapeutics is backed by Amplitude Ventures.

Artios Pharma, a startup developing drugs that weaken a tumor’s ability to maintain its DNA, announced positive results in a subset of patients with advanced cancer. It’s the first big data reveal for the Cambridge, UK-based startup, which has been relatively quiet since 2021, when it struck a drug discovery partnership with Novartis and raised $153 million in Series C financing. The company’s drug, called ART0380, inhibits a DNA repair enzyme called ATR. When administered with a low dose of the chemotherapy irinotecan, the drug shrank tumors in 37% of patients whose cancer was considered “deficient” in another DNA damage response protein dubbed ATM, according to data from a Phase 1/2 study. In patients whose tumors lacked the ATM protein entirely, the response rate was 50%, with a median duration of response of 5.7 months so far. The response rate was 22% in patients with low levels of ATM. Patients with the ATM protein, however, did not respond to the therapy. “All those patients unfortunately progress quickly and unfortunately die very quickly,” Artios Chief Medical Officer Ian Smith told Endpoints News in an interview. The new data, presented Tuesday at the American Association for Cancer Research meeting, comes from 58 patients with advanced-stage and metastatic solid tumors who were treated at the dose the company plans to use in a Phase 2 study. Artios CEO Niall Martin told Endpoints that the company has funds “through 2026.” He said the startup is looking to raise another round of private funding to test its ATR inhibitor in pancreatic and colorectal cancers before pursuing bigger and broader tissue-agnostic studies. Martin said the company’s partnership with Novartis, which wasn’t focused on its ATR inhibitor, identified several targets that could potentially be paired with Novartis’ radioligand therapies, including its prostate cancer drug Pluvicto, and discussions are underway on next steps. Artios had struck a partnership with Merck KGaA in 2020 to search for drugs that target other DNA repair proteins, but Martin told Endpoints that partnership has ended. Artios was founded in 2016 to discover a new wave of drugs that target complex networks of proteins dedicated to the faithful replication and preservation of our genomes. While cancer can survive, and even thrive, with some DNA repair enzymes missing, too many missing pieces can cause the cancer to self-destruct. A class of drugs called PARP inhibitors exploit this vulnerability by blocking the eponymous DNA repair protein in tumors that have mutations in genes called BRCA1 and BRCA2, which are also important for DNA repair. Several companies have been searching for the next combination of targets that can deliver a similar double whammy to tumors, but progress has been slow. “The field hasn’t really evolved much since PARP inhibitors,” Martin said. “So we’ve been really thinking about what are the layers of DNA damage that are created in tumors that could be used as their sort of Achilles heel.” One of those layers, according to Artios, is a phenomenon called replication stress, which can occur when DNA replication, a key step for dividing cells, is blocked. ATR and ATM are two proteins that detect and clear up these blockages. Many forms of chemotherapy obstruct DNA replication. By first inducing a bit more of that stress with a low dose of chemo — but not enough to kill the cancer itself — and then blocking ATR in tumors with little to no ATM, Artios hoped to deliver a triple whammy to tumors. “There’s always been a push to get rid of chemotherapy and have targeted drugs,” Smith said.“But if you can’t get rid of chemotherapy, what you can do is really minimize it. And that’s what we’ve done here.” Smith said the company saw two complete responses, including one in a 62-year-old female who had pancreatic cancer but has been off treatment and cancer-free since August 2023. Neutropenia, a decline in white blood cells, was the most common side effect seen in 53% of patients, with grade 3 neutropenia in 45% of patients. Anemia occurred in 41% of patients. Fatigue, diarrhea, nausea and vomiting were also common side effects. Several other drugmakers have developed their own ATR inhibitors, but lackluster results have caused some pharma companies, including Bayer and Roche, to discontinue or pare back these efforts. “ATR inhibitors have been languishing,” Smith said. “The response rates are low relative to the toxicity that you tend to get.” Roche cut its partnership with Repare Therapeutics in 2024, which paused its ATR inhibitor program earlier this year after modest responses in only 19% and 17% of endometrial and ovarian cancer patients, respectively. Merck KGaA dropped its first ATR inhibitor, berzosertib, but is still testing a second one, called tuvusertib. And AstraZeneca is testing its ATR inhibitor ceralasertib in a Phase 3 study in lung cancer with its immunotherapy Imfinzi, which is expected to complete in August. Artios executives told Endpoints that other ATR inhibitors have faltered for three reasons: the drug’s half-life was too long, leading to intolerable toxicity; the drug was tested as a monotherapy, leading to low efficacy; or the drug was paired with the wrong therapies or tested in the wrong genetic subtypes of cancer. Martin said the company plans to develop a companion diagnostic to identify patients that are most likely to respond to its drug, with an initial focus on ATM. But Artios is looking for other biomarkers that may make tumors vulnerable to ATM inhibitors too. “This whole process of replication stress can be in up to 30% to 40% of tumors,” Martin said. “So there’s a huge area of biology which no one really has tapped into.”

在美国化学会2025年春季会议（ACS）的“首次披露(First-Time Disclosures)”研讨会上，首次公开的 12 种临床候选药物(PCC)的化学结构，包括几款共价抑制剂和PROTAC。这些新分子可能治疗感染、癌症、神经系统疾病和心血管疾病。相关阅读：盘点2024年ACS春季会议新披露的小分子1. LpxC抑制剂：FG-2101（细菌感染）Blacksmith Medicines 公司希望找到可以靶向金属酶的分子。大约三分之一的酶在其活性位点含有金属，因此这是一个丰富的药物发现领域。LpxC 是尿苷二磷酸-3-O-（羟基肉豆蔻酰）-N-乙酰氨基葡萄糖脱乙酰酶，是一种锌水解酶，特异性的存在于革兰氏阴性细菌中。靶向LpxC特异性杀死革兰氏阴性菌可以对抗尿路感染，而不会杀死肠道中的有益细菌。Blacksmith 利用生物无机化学驱动、基于片段的方法，发现了FG-2101这种有效的纳摩尔级抑制剂。FG-2101包含不同的金属结合基序：3-羟基-2-嘧啶酮。FG-2101选择性是其他细菌和人类金属酶的 >10,000 倍，覆盖病原菌谱范围广，并且在动物模型中具有静脉注射和口服活性。它避免了先前异羟肟酸盐 LpxC 抑制剂的毒性，并已完成 IND。2. SMARCA2 PROTAC 降解剂：PRT3789（肿瘤）Prelude Therapeutics　的第一代SMARCA2　PROTAC 降解剂，特异性地降解 SMARCA2，但是需要静脉给药。以合成致死反式治疗　SMARCA4缺乏或发生突变的癌症。大约10%的非小细胞肺癌患者患有SMARCA4缺陷型肿瘤。开发SMARCA2抑制剂挑战是找到一种降解SMARCA2而不是SMARCA4的化合物，它也存在于一些非癌细胞中。SMARCA2和SMARCA4非常保守，均存在一个类似的溴结构域，即介导与其他蛋白质相互作用的蛋白质区域。PRT3789连接子是一个手性甲基，Basch 及其同事认为这是引导降解剂构象的关键，因此它选择性地与SMARCA2和von Hippel-Lindau E3连接酶形成复合物，从而将SMARCA2送至蛋白质降解途径。PRT3789 目前正在与 Keytruda（帕博利珠单抗）联合用于具有 SMARCA4 突变的晚期、复发性或转移性实体瘤患者的 2 期临床试验 （NCT06682806）。3. BCL6 PROTAC 降解剂：BMS-986458（肿瘤）百时美施贵宝的 BMS-986458 靶向BCL6。BCL6是一种参与正常B细胞发育的蛋白质，但在B细胞癌(B 细胞非霍奇金淋巴瘤)中其水平通常会升高。BCL6曾经被认为不可成药。BMS-986458将BCL6 与 与E3泛素连接酶cereblon连接，从而被降解。该化合物表现出快速而深度的 BCL6 降解，与常见的 CRBN 底物相比具有高选择性，并且在体内具有很强的功效。口服给药在淋巴瘤模型中可实现强大的药效。此外，BMS-986458具有三个立体中心，其中一个很容易产生差向异构。这款可口服候选药物目前正在单独、并与抗淋巴瘤药物联合用于复发或难治性非霍奇金淋巴瘤患者中进行1期临床试验 （NCT06090539）。4. PLK4 抑制剂：RP-1664（肿瘤）PLK4 (polo 样激酶 4)是一种存在于某些类型肿瘤中的激酶。Repare Therapeutics的临床候选药物RP-1664的起点是活性本身较高的Centrinone B。在细胞中，Centrinone B 是PLK4的极好抑制剂（Ki 值为 0.59 nM, PMID-25931445）。问题是Centrinone B 代谢迅速且没有生物利用度。因此，Repare的科学家们优化了化合物的ADME性质（吸收、分布、代谢和排泄），并进一步改进了效力。Centrinone B尽管RP-1664和Centrinone B之间存在许多结构差异，但研究人员称，RP-1664中的环丙基取代了Centrinone B中的甲氧基，是该分子效力和选择性的关键。RP-1664处于治疗晚期实体瘤的1期临床试验 （NCT06232408） 中。如果获得批准，它将是同类首创的药物。5. PD-L1 大环肽抑制剂：BMS-986238（肿瘤）百时美施贵宝的Paul M. Scola展示了本次会议最大的临床候选药物。BMS-986238 是该公司的第二代大环肽。第一代的大环肽 BMS-986189，它抑制癌症免疫靶点 PD-L1，但在体内的半衰期较短。第二代大环肽 BMS-986238有低皮摩尔亲和力，长半衰期和可口服生物利用度。为了改善大环肽的药代动力学，该公司的科学家决定在分子中添加一种脂肪酸，使其与血清白蛋白结合并延长其寿命。Wegovy和Zepbound等减肥药使用类似的策略来实现每周给药。研究人员发现，他们必须在脂肪酸和肽大环之间留出空间，因此聚乙二醇链将分子中的这些基团分开。Scola说，这是将肽大环转化为候选药物的良好的通用策略。BMS-986238 可以通过皮下注射每周给药。通过制剂实现的口服给药是每天一次。BMS-986238 最近完成了1期临床试验 （NCT06568458）。6. OX2R 激动剂： ALKS 2680（睡眠障碍）发作性睡病是一种睡眠障碍，其特征是白天过度嗜睡，通常未被诊断出来。Alkermes 的临床候选药物ALKS2680靶向2型食欲素受体（OX2R），它在人体的睡眠-觉醒周期中起着重要作用。其他结合 OX2R 的分子呈C形，因此该公司通过使用共价接头将这种C形构象锁定到位的大环。Alkermes 公司的研究人员Brian Raymer称，“当科学家们构建ALKS 2680 时，非常仔细的设计连接子至关重要”。通过效力和药代动力学的多参数优化，ALKS 2680 可作为每日一次的口服剂量使用。ALKS2680目前正处于多项临床试验中，包括 1 型发作性睡病 （NCT06358950） 的2期试验。7. NKCC1选择性抑制剂：IAMA-6（神经系统疾病）钠-钾-氯协同转运蛋白 1 （NKCC1）与大脑中的氯离子失衡有关。该基因是某些神经系统疾病的标志物，包括自闭症谱系障碍、唐氏综合症和耐药性癫痫。Iama Therapeutics 研究人员称，该项目的挑战在于设计一种不会同时影响NKCC2的分子，NKCC2是一种具有利尿作用的相关蛋白质。IAMA-6 完成这项任务，还可以穿透血脑屏障。在体内，IAMA-6 可恢复氯化物稳态，而没有较早期的 NKCC1 抑制剂（如 bumetanide） 的利尿副作用。IAMA-6 在最近完成了1期临床试验 （NCT06300398）。IAMA-6 可能在2026年开始 2期临床试验。8. EGFR/HER2 Ex20ins 不可逆抑制剂：ORIC-114（肿瘤）EGFR 或HER2外显子20插入的非小细胞肺癌患者通常会在病程中发生脑转移。不幸的是，可用于治疗这些癌症的药物不会穿过血脑屏障。Oric Pharmaceuticals的 Oric-114，是一种高度选择性的，脑部渗透剂，不可逆的 EGFR 和 HER2 外显子 20 插入的抑制剂。ORIC-114是一种通过与这些外显子20插入形成共价键来靶向这些插入突变的分子。Oric Pharmaceuticals的研究人员 Anthony Romero 称 “当你第一次看到这个分子时，你不会认为这是大脑渗透剂”。但该公司已经在其1b 期临床试验 （NCT05315700） 中看到了早期临床的成功。该分子表现出针对 CNS 肿瘤的临床前活性，包括那些具有非典型 EGFR 突变的临床前肿瘤，每天口服剂量在 NSCLC 模型中实现治疗活性。Romero 讲述了试验中一名55岁女性的故事，她有4个脑部病变，在用ORIC-114治疗一轮后消失，她的肺癌在两轮治疗后即出现反应。9. FAP 共价抑制剂：AZD2389（MASH）代谢功能障碍相关的脂肪性肝炎，也称为 MASH，是一种脂肪在肝脏中堆积的疾病。患有MASH的人可能会出现可能致命的肝纤维化。丝氨酸蛋白酶FAP(成纤维细胞活化蛋白 )可能会促进这种纤维化。阿斯利康科学家开发了AZD2389，它通过分子的腈与蛋白质形成共价键来抑制 FAP。在 Cynomolgus Monkey 模型中，AZD2389 导致了纤维化的组织学改善，并进行了良好的耐受性阿斯利康的Anneli Nordqvist表示，导致AZD2389的活动始于探索噻唑烷类化合物。AZD2389 目前在肝纤维化和代偿期肝硬化患者中进行2期临床试验 （NCT06750276）。10. PNPLA3 I148M突变共价抑制剂：PF-07853578（代谢疾病）1-酰基甘油-3-磷酸 O-酰基转移酶 （PNPLA3） 在氨基酸148处携带异亮氨酸-蛋氨酸突变（ I148M）的患者易患更高水平的肝脏脂肪、肝脏炎症、肝硬化和肝癌。研究表明，这是因为这种酶突变体抑制了身体分解脂质的过程。辉瑞开发的PF-07853578，通过与分子氨基甲酸酯基团与PNPLA3 I148M变体共价结合。这种共价相互作用导致从脂滴中去除致病蛋白质，并通过蛋白体诱导蛋白质降解。PF-07853578 已完成1期临床试验 （NCT05890105）。11. Myosin 抑制剂：CK-4021586（心力衰竭）Cytokinetics 合成并测试了2,000 多种化合物，以寻找一种能够结合心脏肌原纤维 ATP 酶（Myosin，心脏中的一种运动蛋白）的分子。他们认为结合这种运动蛋白可以帮助射血分数保留 （HFpEF） 心力衰竭患者，这种疾病的特征是左心室在腔室充满血液期间无法充分放松。CK-4021586具有一种不寻常的氮杂替丁氨基甲醛。CK-586 选择性地靶向肌球蛋白的调节轻链，从而降低收缩性过强的 HFpEF 亚群的收缩性。在发现 CK-4021586 的过程中克服了几个关键的开发障碍：包括谷胱甘肽反应性、活性代谢物形成和高流出等问题。该化合物目前处于2期临床试验 （NCT06793371）。12. 凝血因子  FIIa 和 Xa 抑制剂：BAY 3389934（凝血病）当人们患上脓毒症（对扩散血液的感染的全身反应）时，他们可能会发展出一种影响血液凝固系统的疾病。这种疾病很难治疗，患上它的人通常会死亡。通过阻断这些凝血因子，可能能够缓解与脓毒症相关的凝血病。尽管已经开发了针对这些凝血因子的其他候选药物，但大多数已经停产。拜耳的临床候选药物BAY 3389934，是一种通过静脉给药的两种凝血因子（FIIa 和 FXa）的双重抑制剂。该静脉给药疗法还采用代谢不稳定的酯设计，可快速清除，可严格控制重症监护环境中的抗凝活性。BAY 3389934目前正处于1期临床试验 （NCT06854640），以评估其合适的剂量并研究它如何影响患有脓毒症诱导的凝血病的参与者。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓