TheRas, Inc.

在癌症研究中，RAS-PI3Kα信号通路的异常激活一直是科学家们关注的焦点。这一通路在多种肿瘤中扮演着关键角色，但针对它的药物开发却面临诸多挑战，尤其是如何避免干扰正常的胰岛素信号通路，以及带来的高血糖等副作用。在今天的《科学》论文中，来自弗雷德里克国家癌症研究实验室和BridgeBio Oncology Therapeutics（BBOT）的研究团队报道了一种名为BBO-10203的新型分子。BBOT的新闻稿件指出，这款“first-in-class”口服抑制剂通过阻断RAS-PI3Kα相互作用抑制多种肿瘤生长，且不会诱发高血糖副作用。BBO-10203的发现源于对RAS-PI3Kα相互作用结构的解析。研究团队通过晶体结构分析和分子模拟，设计出能够特异性阻断这一相互作用的化合物，并通过优化其药代动力学性质，最终得到了候选药物BBO-10203。论文指出，BBO-10203能够共价且特异性地结合PI3Kα的RAS结合域，从而阻断HRAS、NRAS和KRAS对PI3Kα的激活。这种作用机制与传统的PI3Kα抑制剂不同，后者通常通过抑制ATP结合位点来阻断酶活性，而BBO-10203则是直接阻止RAS蛋白与PI3Kα的相互作用。研究团队通过结构分析和分子设计，发现BBO-10203能够精准靶向PI3Kα中的半胱氨酸残基（C242），这一位点在其他PI3K亚型中并不存在，因此药物表现出高度选择性。在临床前实验中，BBO-10203展现出了广泛的抗肿瘤活性。它对KRAS或PIK3CA突变的肿瘤，以及HER2过表达的肿瘤均表现出显著抑制效果。值得注意的是，BBO-10203与多种靶向药物联用时效果更佳，例如与CDK4/6抑制剂、ER拮抗剂、HER2抑制剂或KRAS-G12C突变体抑制剂联合使用，能够进一步增强抗肿瘤效果。研究还发现，即使是那些携带KEAP1和STK11突变的难治性肿瘤，也能从这种联合治疗中获益。图片来源：123RF与其他PI3Kα抑制剂相比，BBO-10203的一大优势是其不会引发高血糖副作用。这是因为胰岛素信号通路不依赖于RAS介导的PI3Kα激活来促进葡萄糖摄取。研究团队在小鼠模型中证实，即使在高剂量下，BBO-10203也不会影响血糖水平，而传统的PI3Kα抑制剂则会导致明显的血糖升高。这一特性为BBO-10203的临床应用提供了重要的安全性保障。目前，BBO-10203已进入I期临床试验，用于治疗HR+/HER2-或HER2+乳腺癌、KRAS突变结直肠癌（CRC）以及KRAS突变非小细胞肺癌（NSCLC）患者。这项研究展示了靶向蛋白质相互作用在药物开发中的潜力，为多种癌症的治疗带来潜在新策略。随着临床试验的推进，科学家们将进一步验证这一药物在人体中的安全性和有效性，期待这些发现能够转化为造福众多癌症患者的疗法。参考资料：[1] Dhirendra K. Simanshu et al., BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction. Science (2025). DOI: 10.1126/science.adq2004[2] BBOT Announces Publication in Science Highlighting Preclinical Data that Supports the Potential for RAS:PI3Kα Breaker BBO-10203 to Provide Therapeutic Benefit across Multiple Tumor Types. Retrieved on June 13th, from https://www.businesswire.com/news/home/20250612982572/en/BBOT-Announces-Publication-in-Science-Highlighting-Preclinical-Data-that-Supports-the-Potential-for-RASPI3K-Breaker-BBO-10203-to-Provide-Therapeutic-Benefit-across-Multiple-Tumor-Types欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--TheRas, Inc. d/b/a BBOT (the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, today announced the publication of preclinical data supporting the potential for BBO-10203 to provide therapeutic benefit across multiple tumor types. The publication, titled “BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction” was published in the peer-reviewed journal Science. These data describe the discovery and preclinical evaluation of BBO-10203, a first-in-class, orally available inhibitor that selectively blocks the interaction between RAS proteins and PI3Kα without impairing insulin signaling. By covalently binding to a unique cysteine in the RAS-binding domain of PI3Kα, BBO-10203 effectively disrupts oncogenic RAS-driven activation of the PI3Kα pathway across a range of tumor types, including those with mutations in KRAS, PIK3CA, and HER2 amplification, without inducing hyperglycemia. The compound showed broad antitumor activity in vitro and in vivo and demonstrated enhanced efficacy when combined with targeted therapies such as CDK4/6 inhibitors, ER antagonists, HER2 inhibitors, and KRASG12C inhibitors. These findings support the potential of BBO-10203 as a well-tolerated, mechanistically distinct therapeutic for PI3Kα- and RAS-driven cancers. “Because the contribution of the second most mutated signaling pathway in human cancers remains underappreciated, we searched for an entirely novel molecular mechanism that is not encumbered by known metabolic liabilities to inhibit PI3Kα signaling,” said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. “By blocking the crosstalk between RAS and PI3Kα in tumors, without interfering with physiological insulin signaling, we believe BBO-10203 represents a fundamentally differentiated approach with both biological and therapeutic promise.” “This work stemmed from our goal to elucidate the structural basis of RAS:PI3Kα binding and therapeutically target this interaction,” said Dhirendra Simanshu, PhD, lead author and Principal Scientist at Frederick National Laboratory for Cancer Research (FNLCR). “Our findings show that targeting RAS-effector interactions is both structurally tractable and has potential across a range of cancers. BBO-10203 exemplifies a paradigm shift – rather than inhibiting RAS directly, it intercepts oncogenic signaling through effectors like PI3Kα, enabling tumor suppression while preserving essential physiological functions.” BBO-10203 is currently being evaluated in our Phase 1 BREAKER-101 study (NCT06625775) in patients with locally advanced or metastatic HER2+ breast cancer, HR+/HER2- breast cancer, KRAS mutant advanced CRC, and KRAS mutant advanced NSCLC. The discovery of BBO-10203 was the result of a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT. “This work is an excellent example of chemistry bringing clarity to biology,” said Frank McCormick, PhD, FRS, Chairman of the BBOT Board, Advisor to the National Cancer Institute’s RAS Initiative at Frederick National Laboratory for Cancer Research, and Professor of Tumor Biology and Cancer Research at UCSF. “The role of the RAS:PI3Kα interaction in cancer biology has long been suspected but challenging to pin down precisely. Now we understand which cancers depend on this interaction, some quite unexpected. With BBO-10203 now in the clinic, there's real hope that these discoveries will translate into meaningful benefit for many cancer patients.” About BBOT BBOT is a clinical-stage biopharmaceutical company advancing a next-generation pipeline of novel small molecule therapeutics targeting RAS and PI3Kα malignancies. Initially formed as a subsidiary of BridgeBio Pharma, Inc. (Nasdaq: BBIO), BBOT has the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information, visit bbotx.com.

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (“BBOT” or the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, today announced that the first patient has been dosed with BBO-11818 in the Phase 1 KONQUER-101 trial for advanced solid tumors. BBO-11818 is an orally bioavailable small molecule dual inhibitor that directly binds to both the “ON” and “OFF” states of KRAS. KONQUER-101 will enroll patients globally with certain KRAS mutations. “The dosing of the first patient is a major milestone in assessing BBO-11818’s potential benefit for patients with tumors driven by mutant KRAS,” said Dr. Ignacio Garrido-Laguna, MD, PhD, Principal Investigator at Huntsman Cancer Institute at the University of Utah. “We are committed to bringing cutting-edge therapies to patients with advanced cancer in the Mountain Region. BBO-11818 has the potential to safely achieve optimal target inhibition and combine with other targeted therapies. We look forward to evaluating it in the KONQUER-101 trial.” BBO-11818 was designed to non-covalently bind both the inactive GDP-bound “OFF” and active GTP-bound “ON” forms of KRASG12D and KRASG12V. In cellular assays, EC50 values for pERK inhibition in selected KRAS G12D and G12V-mutant cell lines range from sub-nanomolar to single-digit nanomolar potency. BBO-11818 is similarly effective in reducing cell viability in KRASG12D, KRASG12V, and KRASG12C-mutant cell lines. Further, NRAS and BRAF mutant cell lines show insensitivity to BBO-11818, and the molecule exhibits more than 500-fold selectivity for KRAS over H- and NRAS. “There is a great need for new therapies that can safely treat patients with tumors driven by KRAS mutations, as the current standard of care lacks satisfactory options as monotherapy or to enable combinations of KRAS targeted therapies with other targeted agents,” said Yong (Ben) Ben, MD, Chief Medical and Development Officer of BBOT. “BBO-11818 marks the third molecule entering the clinic for BBOT, further proving our capability to advance novel programs into the clinic. Of note, our portfolio is uniquely positioned to deliver the combination of MAPK (BBO-8520 and BBO-11818) and PI3Kα/AKT (BBO-10203) co-inhibition, with a therapeutic index. We hope this will bring unprecedented benefit to patients with RAS-driven cancers.” The discovery of BBO-11818 was the result of a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT. About BBOT BBOT is a clinical-stage biopharmaceutical company advancing a next-generation pipeline of novel small molecule therapeutics targeting RAS and PI3Kα malignancies. Initially formed as a subsidiary of BridgeBio Pharma, Inc. (Nasdaq: BBIO), BBOT has the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information, visit bridgebiooncology.com.