PERK

SOUTH SAN FRANCISCO, CA, USA I October 30, 2024 I TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (“BBOT” or the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, has announced that the first patient has been dosed with BBO-10203 in the BREAKER-101 trial. BBO-10203 is a first-in-class orally bioavailable RAS:PI3Ka breaker that blocks the interaction between RAS and PI3Kα to inhibit PI3Kα-AKT signaling in tumors, without directly inhibiting the catalytic activity of PI3Kα. “I am thrilled to partner with BBOT to bring a potentially transformable new therapeutic to the clinic,” said Dr. Minal Barve, Chief Medical Officer and Principal Investigator at Mary Crowley Cancer Research, Dallas, TX. “BBO-10203 represents a first-in-class drug with potential to address high unmet medical needs and change the landscape of cancer care. We look forward to evaluating BBO-10203 in the BREAKER-101 trial.” BBO-10203 was designed to bind covalently and selectively to the RAS-binding domain (RBD) of PI3Kα. This selective inhibition is agnostic to the mutational status of PI3Kα and RAS, and in preclinical models, results in complete inhibition of RAS-driven pAKT signal at single digit nanomolar concentration. Additionally, no hyperglycemia was observed in preclinical species treated with BBO-10203. 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. “BBO-10203 is a first-in-class program that inhibits the interaction of the two most mutated oncogenes in human cancer, and it will allow us to test, for the first time, the importance of RAS-coordinated activation of the MAPK and AKT signaling pathways,” said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. “The discovery of BBO-10203 was made possible by the dedicated collaboration between academic, national laboratory, and industry experts that synergized to advance medicines for patients suffering from cancer.” The BREAKER-101 trial will enroll patients globally with locally advanced or metastatic HER2-positive breast cancer, HR-positive/HER2-negative breast cancer, KRAS mutant advanced colorectal cancer, and KRAS mutant advanced non-small cell lung cancer. “There is a tremendous opportunity to improve the standard of care in oncology by inhibiting oncogenic pAKT signaling without the metabolic side effects observed with kinase inhibitors, and the initiation of the Phase 1 study of BBO-10203 marks an important milestone in this regard,” said Yong (Ben) Ben, MD, Chief Medical and Development Officer of BBOT. “The second IND within six months of establishing BBOT clearly demonstrates our team’s capability in advancing our novel programs into the clinic. This novel mechanism and scientific rationale behind it will allow tremendous combination opportunities that optimally inhibit both pAKT and pERK – an approach we hope will bring unprecedented benefit to patients with RAS-driven cancers.” About TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (BBOT) BridgeBio Oncology Therapeutics (BBOT) is a clinical-stage biopharmaceutical company advancing a next generation pipeline of novel small molecule therapeutics targeting RAS and PI3K malignancies. Initially formed as a subsidiary of BridgeBio, BBOT completed a $200M private financing with external investors in 2024 with 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 . SOURCE: BridgeBio Oncology Therapeutics

MIAMI, Sept. 09, 2024 (GLOBE NEWSWIRE) -- Pasithea Therapeutics Corp. (NASDAQ: KTTA) (“Pasithea” or the “Company”), a clinical-stage biotechnology company developing PAS-004, a next-generation macrocyclic MEK inhibitor, for the treatment of neurofibromatosis type 1 (NF1) and other cancer indications, today announced the successful completion of long-term chronic toxicity studies in both rats and dogs with its lead candidate PAS-004, currently being investigated in a Phase 1 clinical trial in advanced cancer patients. Results show that once daily treatment with PAS-004 for 6-months in rats and 9-months in dogs at different dose levels confirms the observations of prior 28-day toxicity studies and indicates a similar safety profile following long-term dosing in both species. Further, the 9-month study in dogs established 0.5 mg/kg as the no adverse effect level (NOAEL) in dogs, the most sensitive species. PAS-004 demonstrated a consistent safety profile at doses that correlate with significant pathway engagement and will likely produce significant pERK reduction when dosed below the NOAEL. Completion of this milestone is planned to support chronic patient dosing. For the chronic toxicity studies, PAS-004 was administered in crystalline form and demonstrated a similar adverse event profile and equivalent NOAEL in dogs as compared to the original amorphous formulation. The Company is using a crystalline form of PAS-004 in its human clinical trials. “It is our belief that the ability to titrate to and obtain sustained Mitogen Associated Protein kinase (MAPK) pathway suppression over a prolonged period will lead to enhanced efficacy with a more manageable side effect profile and less toxicity than that observed with other MEK inhibitors. The results of these long-term chronic toxicity studies further demonstrates PAS-004 safety profile and highlight PAS-004’s potential as a best-in-class MEK inhibitor. We look forward to sharing additional data on PAS-004, including initial interim pharmacokinetic (PK) and pharmacodynamic (PD) data from our first-in-human Phase 1 clinical study later this quarter.” commented Dr. Tiago Reis Marques, CEO of Pasithea. About Pasithea Therapeutics Corp. Pasithea is a clinical-stage biotechnology company focused on the discovery, research and development of innovative treatments for central nervous system (CNS) disorders and RASopathies. With an experienced team of experts in the fields of neuroscience, translational medicine, and drug development, Pasithea is developing new molecular entities for the treatment of neurological disorders, including Neurofibromatosis type 1 (NF1), Solid Tumors, and Amyotrophic Lateral Sclerosis (ALS). Forward Looking Statements This press release contains statements that constitute “forward-looking statements” made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include all statements, other than statements of historical fact, regarding the Company’s current views and assumptions with respect to future events regarding its business, as well as other statements with respect to the Company’s plans, assumptions, expectations, beliefs and objectives, the success of the Company’s current and future business strategies, product development, preclinical and clinical studies, clinical and regulatory timelines, market opportunity, competitive position, business strategies, potential growth opportunities and other statements that are predictive in nature. Forward-looking statements are subject to numerous conditions, many of which are beyond the control of the Company. While the Company believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements, which are based on information available to the Company on the date of this release. These forward-looking statements are based upon current estimates and assumptions and are subject to various risks and uncertainties, including factors set forth in the Company’s most recent Annual Report on Form 10-K, Quarterly Report on Form 10-Q and other filings made with the U.S. Securities and Exchange Commission (SEC). Thus, actual results could be materially different. The Company undertakes no obligation to update these statements whether as a result of new information, future events or otherwise, after the date of this release, except as required by law. Pasithea Therapeutics ContactPatrick GaynesCorporate Communicationspgaynes@pasithea.com

靶向蛋白降解策略通过使用小分子降解剂（如PROTAC），来诱导致病蛋白快速降解，为癌症等疾病的治疗提供了新思路。 体内信号通路如何影响蛋白降解的效果？7月2日，Nature Communications杂志发表了一篇论文，作者确定了调节BRD4、BRD2/3、CDK9等靶点PROTAC靶向降解的细胞信号通路。 他们通过验证，确定了一些化合物——如PDD00017273（一种PARG抑制剂，下文简称PDD)、GSK2606414（一种PERK抑制剂，下文简称GSK)、luminespib（一种HSP90抑制剂)——均是降解增强剂。这些结果表明，各种细胞内在的信号通路在多个步骤影响蛋白降解的效果。 首先，为了确定调节靶向降解的信号通路，研究人员筛选了存在或不存在MZ1（一种基于CRL2VHL的BRD4 PROTAC）的情况下，BRD4降解的变化。结果表明，引入各种细胞内在信号通路后，可能会自发抑制BRD4靶向降解，BRD4可以被特异性抑制剂释放。 图1. 调控BRD4靶向降解途径的筛选 接下来，研究人员分析了HeLa细胞中内源性BRD4的降解。结果发现，PARG抑制PDD可促进BRD4和BRD2/3的靶向降解，但不促进MEK1/2或ERα的靶向降解。 图2. PARG抑制促进BRD4的靶向蛋白降解 在发现PDD对PARG的抑制能显著促进PROTAC诱导的BRD4降解后，研究人员探究了PDD的作用是在哪个步骤起作用的。结果发现，PARG抑制促进BRD4-MZ1-CRL2VHL系列三元复合物形成和K29/K48支链泛素化。此外，研究人员还发现，抑制HSP90可促进BRD4在泛素化步骤后降解。 图3. PARG抑制促进BRD4-MZ1-CRL2VHL系列三元复合物的形成和K29/K48支链泛素化 接下来，研究人员又探索了相关机制，他们发现，PERK或HSP90抑制剂都是主要的蛋白抑制途径，通过影响泛素-蛋白酶体途径的不同步骤来调节BRD4的化学诱导降解。 此外，研究人员还探究了PROTAC增强剂是否可以促进高效降解剂诱导的靶向降解。SIM1是最近开发的一种三价PROTAC，可更有效地诱导BRD-PROTAC-CRL2VHL三元复合物的形成，以及随后BRD4和BRD2/3的降解。结果发现，使用SIM1+PDD或SIM1+GSK的共同治疗，比单独使用SIM1的治疗更有效地诱导细胞死亡。 最后，研究人员想知道，这些信号抑制剂是否也促进其他激酶（如CDK9）的活性，结果发现，PARG抑制不仅可以有效降解BRD家族蛋白，还可以降解CDK9。 论文作者表示：“我们预计随后的筛选会鉴定出许多细胞通路，这些通路的鉴定将有助于阐明靶向蛋白质降解的机制。” 注：文章配图均来自论文 参考资料： Yuki Mori et al. Intrinsic signaling pathways modulate targeted protein degradation. Nature Communications（2024） https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-49519-z Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。 免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。