Design, Synthesis, Anticancer Evaluation and Molecular Docking of Pyrimidine, Pyrido[4,3-d]pyrimidine and 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine Derivatives as Novel KRAS-G12D Inhibitors and PROTACs

Article

作者: Yang, Hailong ; Gan, Lu ; Zhang, Huabei

Background: KRAS-G12D mutations drive 20–50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure–activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine/pyrido[4,3-d]pyrimidine/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based drug design. Antiproliferative activity against KRAS-G12D (Panc1), KRAS-G13D (HCT116) and wild-type (A549) cells was assessed using the CCK-8 assay. KRAS-G12D enzymatic inhibition was measured using a GTPase activity assay. Molecular docking simulations (Sybyl 2.0; PDB:7RPZ) elucidated binding modes. Two PROTACs were synthesized from lead compounds by conjugating E3 ligase linkers. All the novel inhibitors and PROTACs were characterized by means of NMR or HRMS. Results: Compound 10c demonstrated selective anti-proliferation in Panc1 cells (IC50 = 1.40 μM) with 4.9-fold greater selectivity over wild-type cells, despite weak enzymatic inhibition (IC50 > 10 μM). Docking revealed critical hydrogen bonds between its protonated 3,8-diazabicyclo[3.2.1]octane moiety and Asp12/Gly60. The enzymatic inhibitor 10k showed potent KRAS-G12D inhibition (IC50 = 0.009 μM) through homopiperazine-mediated interactions with Glu92/His95. Derived PROTACs 26a/b exhibited reduced potency (IC50 = 3–5 μM vs. parental 10k: 2.22 μM), potentially due to impaired membrane permeability. Conclusions: Eleven novel KRAS-G12D inhibitors with a seven-membered ring pharmacophore were synthesized. Compound 10c showed strong anti-proliferative activity, while 10k exhibited potent enzymatic inhibition. Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development.

项与 KRAS G12D inhibitors (Shenzhen Forward Pharmaceuticals) 相关的新闻（医药）

2025-08-12

·新药猎人笔记

1.3亿美元预付款！拜耳引进一款处于临床1期的KRAS G12D抑制剂

2025年8月12日，拜耳公司（Bayer）宣布与Kumquat Biosciences宣布达成一项全球独家许可和合作协议，共同开发一款针对KRAS G12D突变的精准抗癌药物。该协议的总价值高达13亿美元，标志着拜耳在精准肿瘤学领域的又一重大布局。 KRAS是一种在多种癌症中频繁出现的致癌基因，其中KRAS G12D突变在胰腺癌、结直肠癌和肺癌等实体瘤中尤为常见。尽管KRAS一直是癌症治疗的重要靶点，但由于其蛋白结构的特殊性，开发有效的KRAS抑制剂一直是科学界的难题。此次合作开发的KRAS G12D抑制剂有望为携带该突变的癌症患者提供新的治疗选择。图源：https://pmc.ncbi.nlm.nih.gov/articles/PMC11912584/ KRAS G12D突变在37%的泛肝癌导管无癌无癌（PDAC）病例、13%的结肠直肠肿瘤和4%的非小细胞肺癌中被发现。拜耳公司说，PDAC是最难治疗的肿瘤之一，患者的五年生存率不到10%。根据协议，Kumquat Biosciences将负责该药物的早期研发工作，直至完成首次人体试验（FIH）。拜耳则将利用其在药物开发和商业化方面的丰富经验，负责该药物的全球开发和商业化。拜耳将向Kumquat Biosciences支付1.3亿美元的预付款，并在达到特定的临床和商业里程碑后支付高达12亿美元的额外款项。拜耳全球战略业务发展与许可负责人表示：“此次合作进一步巩固了拜耳在精准肿瘤学领域的领导地位。通过与Kumquat Biosciences的合作，我们能够将KRAS G12D抑制剂纳入我们的研发管线，为患者提供更精准的治疗方案。” 结束语：目前，KRAS G12D临床开发最快的是Revolution medicine和劲方医药的KRAS G12D抑制剂。其中Zoldonrasib在18例可评估疗效的NSCLC患者中，客观缓解率达到61%，疾病控制率达到89%。劲方医药的NSCLC的ORR为42%，PDAC的ORR为52%。数据来源：deepseek检索

引进/卖出临床1期临床2期

2025-08-12

·药研网

重磅！拜耳达成13亿美元协议合作

2025年8月12日，拜耳与临床阶段生物科技公司 Kumquat Biosciences 共同宣布，双方已达成一项重磅的全球独家许可与合作协议。双方共同开发和商业化 Kumquat Biosciences 的 KRAS G12D 抑制剂，旨在为胰腺癌、结直肠癌和肺癌患者带来新的治疗希望。 Kumquat已于2025年7月获得美国FDA对其 KRAS G12D 抑制剂的临床试验申请许可。根据协议条款，Kumquat Biosciences 将获得高达13亿美元的总付款，其中包括前期款项、临床及商业里程碑付款，以及额外基于净销售额的分级特许权使用费。Kumquat Biosciences 还保留了在美国参与利润亏损分成的独家谈判选择权。此次与 Kumquat Biosciences 的合作，进一步丰富拜耳在精准肿瘤学方面的早期研发管线。 Kumquat Biosciences 首席执行官 Yi Liu 表示，此次合作不仅验证了 Kumquat Biosciences 平台的实力以及其 KRAS G12D 候选药物解决肿瘤学领域长期未满足需求的潜力，还为 Kumquat Biosciences 提供了财务资源，以加速其更广泛的临床管线发展。 Kumquat致力于为癌症患者创造改变生命的药物。该公司成立于2019年，由 OrbiMed、HSG、EcoR1、Lilly Asia Ventures、Roche Venture Fund 和 Boxer Capital 等机构资助，此前已与礼来和武田达成了两项重大合作。 End 声明：本公众号所有发文章(包括原创及转载文章)系出于传递更多信息之目的，且注明来源和作者。本公众号欢迎分享朋友圈或大群，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载/商务/投稿 | 联系微信15618157102（sum_Gmi）商务合作稿件征集点击了解详情往期回顾 1 港股创新药走出至暗时刻 2 License-out潮来袭：谁是下一个出海爆款? 3 高盛发声：中国创新药价值重估时代来临

2025-08-12

·BioSpace

Bayer Makes Potential $1.3B Cancer Bet in Kumquat Deal

iStock, SiyueSteuber For $1.3 billion in aggregate—including upfront and milestone payments—Bayer will get exclusive global access to Kumquat Biosciences’ small-molecule KRAS G12D blocker. Bayer is putting up to $1.3 billion on the line to partner with San Diego–based Kumquat Biosciences and advance its KRAS G12D inhibitor for a variety of oncology targets. The companies did not reveal a specific financial breakdown for the transaction, only noting that the $1.3 billion sum encompasses an upfront commitment plus clinical and commercial milestones down the line. Kumquat will also be eligible for tiered royalties on net sales of the cancer drug if it reaches the market, according to the announcement Tuesday. For its investment, Bayer will gain exclusive rights over Kumquat’s investigational KRAS G12D inhibitor, which last month won the FDA’s blessing to start clinical studies. Kumquat will be responsible for seeing the drug through Phase Ia development. Bayer will be in charge of completing the molecule’s clinical development from there and for running its regulatory and market activities. As per the terms of Tuesday’s pact, Kumquat will also have the option to negotiate with Bayer for a profit-loss sharing arrangement in the U.S. In a prepared statement, Juergen Eckhardt, head of Business Development and Licensing at Bayer’s Pharmaceuticals Division, said that the partnership with Kumquat will not only allow the pharma to “explore . . . a potential new treatment option” for patients with cancer but also give it a precision asset that complements its own oncology portfolio. Bayer’s oncology activities are anchored by the androgen receptor blocker Nubeqa, which was first approved in 2019 for non-metastatic castration-resistant prostate cancer. The drug picked up another indication in June this year for metastatic castration-sensitive prostate cancer with or without chemotherapy. Bayer is also working on sevabertinib, which is currently under the FDA’s priority review for HER2-mutant non-small cell lung cancer. With Kumquat, Bayer plays catch-up to Revolution Medicines, which is also targeting KRAS G12D with its drug candidate zoldonrasib. Phase I data released in April demonstrated “preliminary tumor activity,” the biotech noted at the time, with an objective response rate of 61% in 18 evaluable patients. Last week, Revolution revealed plans to take zoldonrasib into pivotal development next year. For Kumquat, Bayer is its third powerhouse partner. In July 2021, the biotech linked up with Eli Lilly’s Loxo Oncology in a partnership to develop small molecule cancer drugs. That deal entailed a $70 million upfront payment from Lilly and milestones of up to $2 billion. In April 2024, Kumquat received $130 million upfront from Takeda for one of its small molecule immuno-oncology inhibitors for an undisclosed oncology target. Takeda tacked on more than $1.2 billion in milestones.

临床1期上市批准优先审批引进/卖出

100 项与 KRAS G12D inhibitors (Shenzhen Forward Pharmaceuticals) 相关的药物交易

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