A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of BGC515 Capsules in Patients With Advanced Solid Tumors

The goal of this open-label, dose escalation and dose expansion Phase I clinical trial is to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of BGC515 administered once daily in 3 weeks cycles in solid tumor patients.

开始日期2024-06-27

申办/合作机构

Bridgene Biosciences, Inc.

100 项与 Bridgene Biosciences, Inc. 相关的临床结果

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0 项与 Bridgene Biosciences, Inc. 相关的专利（医药）

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项与 Bridgene Biosciences, Inc. 相关的文献（医药）

2024-05-02·Cancer Research

Abstract PO3-06-13: A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer

作者: Oluwalana, Damilola ; Chen, Hao ; Hartman, Kelli ; Miller, Duane ; Playa, Hilaire ; Krutilina, Raisa ; Seagroves, Tiffany ; Deng, Shanshan ; Parke, Deanna ; Li, Wei

AbstractBackground: Improving survival for patients diagnosed with metastatic disease and treating spontaneous chemoresistance remain major clinical challenges in treating breast cancer. Triple negative breast cancer (TNBC), characterized by a lack of therapeutically targetable receptors (ER/PR/HER2), is an aggressive subtype of breast cancer. TNBC therapy relies on a combination of systemically administered chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA approved MTAs that bind to the colchicine-binding site. Approximately 70% of patients who initially respond to paclitaxel, a first-line MTA, will develop taxane resistance (TxR) within 6 months. We have previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), sabizabulin (formerly known as Veru-111), not only inhibits TNBC tumor progression but also treats pre-established metastatic disease in a taxane-refractory PDX model, HCI-10-Luc2. Sabizabulin is currently in phase II/III trials for advanced prostate cancer. To further improve potency and metabolic stability, we created next-generation derivatives of the sabizabulin scaffold, including 60c. Results: 60c shows improved potency compared to sabizabulin against taxane-sensitive and TxR TNBC models, inhibiting proliferation and clonogenicity at low nanomolar concentrations, and inducing apoptosis in a dose-dependent manner. In vivo, 60c therapy significantly suppressed primary tumor growth and lung metastasis in an orthotopic MDA-MB-231-TxR xenograft model without gross toxicity, and with equivalent efficacy to combrestatin A4 phosphate (CA-4P), another CBSI in clinical trials. In the taxane-refractory HCI-10-Luc2 PDX model, 60c significantly suppressed both the growth of the primary tumor (by ~3.5 fold) and the expansion of pre-established axillary metastases (by ~26 fold) whereas paclitaxel had no effect. Analysis of total photon flux of organs excised at study endpoint showed that 60c had distinct anti-metastatic tropism as compared to sabizabulin. Whereas 60c completely suppressed metastases to the spleen (0/9 mice had signal), and significantly reduced metastatic burden in the leg bones (only 3/9 mice had signal) and in the kidney (only 2/9 mice had signal), 60c had no statistically significant effect on liver metastases. In contrast, we had previously reported that sabizabulin strongly repressed liver metastases in the same PDX model (0 mice with detectable liver metastases), with less potent effects on bone. Unlike 60c, sabizabulin showed no improvement relative to the vehicle control for spleen and kidney metastases. Together, our data positions 60c as a promising candidate for TNBC therapy, particularly for patients with TxR disease. Our results also suggest that different CBSI scaffolds may preferentially inhibit metastasis to specific organs, which requires further investigation.Citation Format: Damilola Oluwalana, Kelli Hartman, Raisa Krutilina, Hao Chen, Hilaire Playa, Shanshan Deng, Deanna Parke, Duane Miller, Tiffany Seagroves, Wei Li. A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-13.

2023-04-04·Cancer Research

Abstract 4976: Preclinical characterization of BGI-9004, a covalent TEAD inhibitor with exceptional anti-cancer activity and combination potential

作者: Wiedemeyer, Wolf R. ; Dong, Iris ; Chen, Anna ; Zhang, Vivian ; Cui, Jason ; Sperandio, David ; Guo, Shirley ; Cao, Ping ; Luo, Steve ; Shrishrimal, Shashank ; Deng, Ning ; Wang, Guoqing

AbstractPharmacological inhibitors of TEAD transcription factors have emerged as a promising novel class of anti-cancer agents. TEAD inhibitors disrupt oncogenic YAP/TAZ signaling, resulting in cell cycle arrest and cell death in susceptible cancers. In preclinical models, cancer cell lines with alterations in the Hippo signaling pathway, such as mutations or loss of NF2 or LATS, are particularly sensitive to inhibition of TEAD signaling. In addition, YAP/TAZ-TEAD signaling is thought to play a role in resistance to several targeted therapies, such as EGFR inhibitors and MEK inhibitors. BGI-9004 is a covalent inhibitor of TEAD1-4 with low nanomolar potency in a TEAD reporter cell line and anti-cancer activity in vitro and in vivo. In the NF2-deficient NCI-H226 and the NF2-wildtype, LATS-mutant MST-O211H mesothelioma xenograft models, BGI-9004 treatment resulted in sustained tumor regressions over a 28d treatment course. Anti-cancer activity was accompanied by significant inhibition of TEAD-mediated transcription in BGI-9004-treated tumors, and no adverse effects on the body weight of treated mice were observed. Moreover, proteome-wide protein binding of BGI-9004 was assessed by Isobaric Mass Tagged Affinity Characterization (IMTACTM), which confirmed its high selectivity for TEAD. In line with this, BGI-9004 had a clean profile in a panel of protein targets that present potential safety liabilities (CEREP safety panel). These findings prompted us to explore the combination potential of BGI-9004 with other targeted therapies, including inhibitors of EGFR, MEK and mutant KRASG12C. Here, we found that BGI-9004 potentiated the effect of other targeted therapies. In particular, we generated dose response matrices for BGI-9004 and inhibitors of KRASG12C and KRASG12D in several KRAS-mutant cell lines, including three lung cancer cell lines, and demonstrated synergy for the combination. These results suggest that inhibition of YAP/TAZ-TEAD signaling may improve the efficacy of KRAS-targeted therapy. Taken together, the covalent TEAD inhibitor BGI-9004 has demonstrated promising activity both as a single agent and in combination with other targeted agents, a favorable pharmacokinetic profile and high target selectivity in preclinical models, supporting its evaluation as a novel anti-cancer agent in clinical trials.Citation Format: Shirley Guo, Shashank Shrishrimal, Jason Cui, Guoqing Wang, Vivian Zhang, Ning Deng, Iris Dong, Anna Chen, Steve Luo, David Sperandio, Ping Cao, Wolf R. Wiedemeyer. Preclinical characterization of BGI-9004, a covalent TEAD inhibitor with exceptional anti-cancer activity and combination potential. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4976.

2021-12-01·Molecular Cancer Therapeutics

Abstract P221: Discovery of a covalent inhibitor for an oncogenic mutant RhoAY42C

作者: Guo, Shirley ; Cao, Ping

AbstractRas homolog family member A (RhoA) is a member of a larger family of Rho proteins of small GTPases, with structural and signaling similarities to Ras proteins. RhoA is involved in multiple cellular processes including cytoskeleton regulation and actin-myosin contractility, etc. Recent studies have shown that the most common RhoA mutation in diffuse gastric cancer (DGC), Y42C, causes a gain-of-function and is associated with the loss of the E-cadherin gene CDH (CDH1). Inhibitors of RhoAY42C could be promising agents for treating DGC that harbors CDH1 mutation/deletion. BridGene expressed RhoAY42C in cells, screened our proprietary covalent library against the RhoAY42C live cells, and employed our chemoproteomic platform IMTACTM (Isobaric Mass Tagged Affinity Characterization) to detect covalent labeling of the mutant RhoA protein. A pilot screening led to the successful identification of a covalent ligand of RhoAY42C, BGS1933. Mass spec analysis has confirmed the covalent modification of Cys42 in RhoA by BGS1933. Dose-dependent binding of BGS1933 to RhoAY42C was measured using an orthogonal fluorescence-based assay. The Cancer Genome Atlas (TCGA) study shows that ~1% DGC patients harbor the oncogenic mutant RhoAY42C. The discovery of a covalent inhibitor of RhoAY42C will enable us to validate the role of RhoAY42C in DGC and facilitate the development of new first-in-class targeted therapies for the treatment of gastric cancer.Citation Format: Shirley Guo, Ping Cao. Discovery of a covalent inhibitor for an oncogenic mutant RhoAY42C [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P221.

项与 Bridgene Biosciences, Inc. 相关的新闻（医药）

2024-10-09

·PRNewswire

BridGene Biosciences to Present Three Novel Covalent Inhibitors at the 36th EORTC-NCI-AACR Symposium

Presentations on cMyc, ADAR1, and PAX8 inhibitors to be held on October 25, 2024 SAN JOSE, Calif., Oct. 9, 2024 /PRNewswire/ -- BridGene Biosciences, a leader in the discovery of small molecule drugs for traditionally "hard-to-drug" targets, today announced it will present three groundbreaking posters at the American Association for Cancer Research (AACR) 2024 Annual Meeting in Barcelona, on October 25, 2024. The posters will showcase the company's latest advancements in the development of covalent inhibitors for key oncogenic targets, including cMyc, ADAR1, and PAX8, each representing promising new treatment avenues for various cancers. "These three presentations represent significant strides in our mission to develop novel therapeutics for cancer patients," said Ping Cao, Ph.D., Co-Founder and CEO of BridGene Biosciences. "By focusing on these high-value, historically hard-to-drug targets, we aim to create first-in-class therapies that address critical gaps in cancer treatment. Our platform continues to unlock new possibilities in drug discovery, and we are excited to share these advancements with the scientific community at AACR." BridGene's work on cMyc, titled "Discovery of a Covalent Inhibitor Targeting the Undruggable Oncogene cMyc," focuses on overcoming the challenges posed by its intrinsically disordered structure, which has historically rendered the protein hard-to-drug. Through its proprietary Isobaric Mass Tagged Affinity Characterization (IMTAC™) platform, BridGene identified two hit compounds, which effectively inhibit cMyc signaling. These inhibitors showed potent activity in reducing transcriptional function and offering a potential therapeutic strategy for cancers driven by cMyc amplification, which accounts for nearly one-third of all tumors. In addition to its work on cMyc, BridGene will present research titled "Discovery of a Novel Covalent ADAR1 Inhibitor," focusing on a novel covalent inhibitor targeting ADAR1, an enzyme that plays a critical role in RNA editing and immune suppression in cancer. By inhibiting ADAR1, BridGene's compounds, could be expected to enhance the efficacy of immune checkpoint blockade therapies. This research highlights the potential for ADAR1 inhibitors to reshape the tumor microenvironment, paving the way for more effective immunotherapies. BridGene's third poster presentation, "Discovery of a Novel Covalent PAX8 Inhibitor," will unveil a covalent inhibitor of PAX8, a transcription factor linked to poor prognosis in renal cell carcinoma and ovarian cancer. Utilizing its IMTAC™ platform, BridGene discovered a compound that disrupts the DNA binding activity of PAX8. This discovery opens the door to new therapeutic strategies for cancers with elevated PAX8 expression, which have traditionally been difficult to target. About BridGene Biosciences BridGene is a biotechnology company focused on discovering and developing innovative small molecules that drug traditionally undruggable targets, providing new paths to treat diseases. By using its proprietary chemoproteomic platform, IMTAC™, BridGene can screen small molecules against all proteins in live cells to discover drug candidates for high-value and previously undruggable targets. BridGene is advancing a diversified pipeline of first-in-class drugs for targets in multiple disease areas. For more information, visit . Contact Tiberend Strategic Advisors, Inc. Jonathan Nugent (investors) 205-566-3026 [email protected] Dave Schemelia (media) 609-468-9325 [email protected] SOURCE BridGene Biosciences WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

AACR会议免疫疗法

2024-08-02

·药渡

近9亿美元！一项针对靶向SMARCA2 PROTAC的交易刚刚达成

2024年8月1日，BridGene Biosciences（简称“BridGene”）宣布，公司扩大与Galapagos的战略合作和许可协议；重点是发现一种高度选择性的口服SMARCA2蛋白降解靶向嵌合体 (PROTAC)。依据本次合作，BridGene 将利用其 PROTAC 发现引擎与 Galapagos 在选择性 ATPase 小分子方面的专业知识相结合；旨在将合作分子推进为临床前候选药物，Galapagos拥有进一步开发和商业化合作分子的独家权利。根据协议条款，本次Galapagos 将向 BridGene 提供前期和临床前里程碑付款，以及基于临床和商业里程碑的额外付款，潜在交易总价值高达 1.59 亿美元；BridGene 还有资格获得合作产品净销售额的分级版税。双方曾于2024年1月签订了一项潜在总金额约7.27亿美元的合作协议，针对特定靶点发现新型小分子候选药物；此次扩大合作后，累计总交易金额近9亿美元。关于SMARCA2药物 SMAECA2/4是SWI/SNF复合物中非常重要的催化亚基，对于SWI/SNF活性至关重要，例如细胞代谢（包括药物代谢）、分化、发育、DNA修复、肿瘤生成、转移。SMARCA4在几种癌症类型中均有发生突变，而SMARCA2突变在癌症中很少见，研究表明，SMARCA4纯合突变体的小鼠不能存活，而SMARCA2/4中SMARCA4突变的小鼠，可以存活，存在“合成致死”关系。图片来源：Prelude官网 SMARCA2对于SMARCA4中具有功能丧失突变的肿瘤细胞生长至关重要，是SMARCA4突变癌症中关键且有希望的治疗靶点。此外，SMARCA4缺陷的患者群体通常缺乏可靶向的癌基因（如突变的EGFR或ALK易位），这进一步强调了开发SMARCA2抑制剂的潜力。据不完全统计，目前在研的SMARCA2药物约二十余种；其中国内企业先声（SCR-9140）、赞荣、信诺维均在该领域进行布局。关于BridGene BridGene是一家专注于发现和开发创新小分子药物的生物技术公司，借助其特有的化学蛋白质组学平台IMTAC，针对那些具有高价值、传统上被认为“难以成药”的靶点开发新的治疗药物。 IMTAC技术平台不仅可以在活细胞中发现大量靶标的小分子配体，且可以与表型筛选技术结合以确定驱动表型变化及疾病发生的靶标。该平台通过一个独有的类药共价小分子库进行活细胞筛选，小分子会在活细胞中与其中一部分蛋白结合。此外，通过定量质谱能分析与小分子结合的候选蛋白及其结合后的相对亲和力，以识别出活细胞中与化合物结合的靶标（通过表型筛选获得）及其相对结合亲和力，从而发现能够驱动疾病的新靶标。除Galapagos外，公司曾于2021年3月与武田就IMTAC技术平台开发小分子药物达成交易，交易金额高达5亿美元。关于Galapagos Galapagos 是一家生物技术公司，致力于开发转化药物，以延长寿命并提高生活质量。公司专注于在肿瘤学和免疫学领域打造一流的小分子、细胞疗法和生物药物管线。关于2024年靶向蛋白降解领域的交易据不完全统计，截至目前，本年度靶向蛋白降解领域交易共发生十余笔。参考资料 1、公司官网 2、Being科学药渡媒体商务合作媒体公关 | 新闻&会议发稿张经理：18600036371（微信同号）点击下方“药渡“，关注更多精彩内容免责声明 “药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！👇👇👇

蛋白降解靶向嵌合体引进/卖出

2024-08-02

·BioBAY

9亿美元！桥济生物达成一项平台合作

8月1日，BioBAY园内企业BridGene Biosciences（桥济生物）宣布与Galapagos NV（Euronext & NASDAQ: GLPG）扩展其战略合作和许可协议。此项合作建立在1月合作基础上，专注于开发高度选择性的口服SMARCA2小分子蛋白质降解化合物（PROTAC）。 2024年1月，BridGene与Galapagos签订了一项总金额超过7亿美元的合作协议，BridGene将运用其前沿的IMTAC™化学蛋白质组学平台，针对特定靶点发现新型小分子药物候选物。此次双方进一步扩大合作，将总金额提升至近9亿美元。作为共价小分子药物开发的领导者，BridGene专注于为传统“难以成药”靶点开发药物。根据扩展协议的条款，BridGene将利用其先进的PROTAC探索平台，并结合Galapagos在选择性ATPase小分子方面的专业知识，共同推进该分子至临床前候选阶段。Galapagos将拥有进一步开发和商业化的独家权利。 Galapagos将向BridGene提供预付款和临床前里程碑付款，以及基于临床和商业里程碑的额外付款，交易总价值将高达1.59亿美元。此外，BridGene还有资格获得根据合作产生的每个产品的净销售额分级版税。此次合作的拓展，进一步印证BridGene创新药物发现平台的实力，凸显了战略合作在加速药物研发进程中的核心价值。BridGene与Galapagos共同致力于开发突破性的精准药物，旨在显著提升患者治疗效果，利用靶向蛋白降解技术，满足癌症领域内迫切且未被满足的医疗需求。 BridGene联合创始人兼首席执行官Ping Cao博士表示： “我们很高兴能加深与Galapagos的合作，这将使我们能够开发更多针对高价值且具有挑战性的肿瘤靶点的新药。Galapagos在肿瘤领域的科学专业知识与我们的技术能力完美契合。此次合作将进一步加强我们在发现难以成药靶点药物方面的卓越纪录。我们的目标是通过结合我们的创新药物发现平台和Galapagos的研发及临床专长，大幅提升药物研发的成功率。” Galapagos小分子药物开发高级副总裁兼负责人Pierre Raboisson博士表示，“我们很高兴能够扩展与BridGene Biosciences的合作。BridGene在对难以成药靶点的药物发现方面拥有强大的专业能力。我们的扩展合作充分发挥了双方的独特优势，将我们内部药物开发专长与BridGene尖端的PROTAC技术平台相结合，致力于为急需解决方案的癌症患者带来精准治疗。” ▌文章来源：动脉网责编：何文正审核：任旭推荐阅读企业资讯丨拓展亚太市场，英矽智能与韩国Therasid Bioscience签署战略合作企业资讯丨微光基因与Lakeshore Biotechnology达成全球合作企业资讯丨玉森新药：与葫芦娃药业集团签署合作协议——推动中药创新药现代化发展

蛋白降解靶向嵌合体引进/卖出

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药物(靶点)	适应症	全球最高研发状态

BGC-515 ( TEAD )	上皮样血管内皮瘤更多	临床1期
TEA domain transcription factors inhibitors (BridGene ) ( TEAD )	肿瘤更多	临床前
BGS-1989 ( WDR5 )	肿瘤更多	临床前
BGS1949 ( ZAP70 )	-	临床前
60c(BridGene) ( TUB )	三阴性乳腺癌更多	临床前