CellCentric Ltd.

近日，中国科学院广州生物医药与健康研究院许永研究员课题组报道了一种新型的、高效的靶向CBP/p300的PROTAC降解剂，可用于治疗急性髓系白血病（Acute myeloid leukemia，AML）。相关成果近日以“Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity”为题发表在美国化学会（ACS）Journal of Medicinal Chemistry上。 AML是常见的血液恶性肿瘤之一，严重威胁患者的生命健康。AML患者的五年总生存率低于40%，而且发病率随着年龄的增长而增加。因此，临床上亟需开展基于新靶标、新机制的抗AML药物研究。环磷酸腺苷反应元件结合蛋白（CREB）结合蛋白（CREBBP，CBP）及其高度同源的腺病毒EA1结合蛋白（EP300，p300）作为转录共激活因子与AML的发生发展密切相关。近20多年来，许多CBP/p300小分子抑制剂被报道。其中，CellCentric公司开发的CCS1477率先进入临床1/2期研究，用于白血病、前列腺癌等癌症的治疗。然而，目前还没有相关药物上市。许永团队长期致力于CBP/p300小分子抑制剂的研究，并获得了系统性的研究成果（Eur. J. Med. Chem. 2018；Acta Pharmacol. Sin. 2019；J. Med. Chem. 2022；Bioorg. Chem. 2024）。然而，CBP/p300小分子抑制剂会面临两个问题：（1）化合物长期暴露会导致耐药；（2）化合物单独靶向CBP/p300的HAT或BRD域可能无法完全消除其功能。因此，迫切需要一种新的策略，以获得更有效的治疗。蛋白降解靶向嵌合体（PROteolysis TArgeting Chimeras，PROTAC）是一种利用小分子来调节蛋白水平的靶向蛋白降解技术。PROTAC分子可以诱导靶蛋白与E3连接酶相互靠近并，使靶蛋白被泛素化，之后被蛋白酶体降解。在本研究中，我们选择CCS1477作为CBP/p300的配体，沙利度胺作为E3连接酶CRBN的配体，设计合成了系列CBP/p300 PROTAC分子（图1）。通过系统的构效关系研究和生物活性评价，该团队发现了两个高活性的具有双芳香环Linker的CBP/p300降解剂XYD190和XYD198（图2）。这两个降解剂可有效抑制AML细胞系MV4;11的增殖（IC50分别为1.8 nM和0.9 nM），并以CRBN和蛋白酶体依赖的方式高效地降解CBP和p300蛋白（DC50 < 2 nM）（图2）。蛋白质组学研究表明，XYD190和XYD198可有效下调CBP/p300蛋白，并且对其它溴结构域家族和分子胶底物的蛋白水平无明显影响。在MV4;11异种抑制瘤模型中，XYD190和XYD198可显著抑制肿瘤的生长（TGI分别为88%和93%）（图2）。本研究为AML的治疗提供了一种采用新的作用机制的更优的候选药物。广州健康院许永研究员和张岩副研究员为共同通讯作者，许永课题组博士研究生胡建康、硕士研究生徐鸿瑞和博士研究生吴天帮为本论文的共同第一作者。该研究得到了国家重点研发计划，国家自然科学基金，广东省基础与应用基础研究项目，广州市科技计划项目，广东省“一带一路”联合实验室基金，中科院STS项目，中国博士后科学基金，广东省博士后专项的支持。图1. 靶向CBP/p300的PROTAC降解剂的设计策略图2. XYD190和XYD198的结构及活性数据声明：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↓

UK-based biotech, CellCentric which spun out of Cambridge University has today (December 11) announced new clinical data for the drug at the American Society for Hematology (ASH) in San Diego. The results follow a recent publication in the Cancer Cell journal, which describes the novel mechanism of action of inobrodib, a first in a new class of drug – an oral agent.  The drug disrupts the action of p300/CBP at regulatory elements controlling key cancer genes. Inobrodib impacts the expression of IRF4 and MYC, two potent oncogenes that drive multiple myeloma. The mechanism is clearly differentiated from that of other commonly used drugs, and it has also been proven to be synergistic to agents such as the IMiDs.  As now shown clinically, patients refractory to pomalidomide become responsive to inobrodib combined with pom + dex. “We are pleased that clinical activity of this combination is so encouraging in last-line patients, confirming the potential of this new approach,” said Tomasz Knurowski, chief medical officer at CellCentric. “Further evaluation is underway, but there are clear signs that targeting p300/CBP to treat haematological malignancies, including myeloma, has the potential to address unmet medical need.” The data has been derived from heavily pre-treated patients, who are mostly triple-class refractory (when the disease does not respond to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies), with a median of five lines of prior therapy who have been taking part in a multi-center phase 1/2a clinical ​ trial. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Data were shared at ASH from two combination cohorts at doses of inobrodib at 25mg or 35mg twice daily on a four days on / three days off intermittent schedule, with standard dosing of pom + dex in 28-day cycles. The results showed inobrodib has a manageable safety profile.  All patients demonstrated some signs of clinical activity, with rapid responses - 72% greater than or the same as MR by IMWG criteria in both cohorts and 67% ORR in the 35mg cohort.  A significant number of patients across both dosing cohorts remain on treatment after six months. CellCentric has previously reported initial monotherapy tolerability and efficacy data, at ASH 2022. Emma Searle, consultant haematologist at The Christie NHS Foundation Trust, who has overseen the care of many of the patients on the clinical trial, added: “The results show promising efficacy data in relapsing-remitting multiple myeloma patients who have exhausted standard-of-care therapies, both as a monotherapy and in combination with pom + dex. Further trials continue to refine dosing and expand the cohort.” Multiple myeloma, also known as myeloma, is a type of bone marrow cancer. Bone marrow is the spongy tissue at the center of some bones that produces the body's blood cells. It is called multiple myeloma as the cancer often affects several areas of the body, such as the spine, skull, pelvis and ribs.

CellCentric, a UK-based biotechnology company, announced today (November 22) the publication of the paper and how the work builds on pre-clinical and clinical collaborations, notably with Professor Tim Somervaille of the Cancer Research UK Manchester Institute. The paper, titled, Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies ​ ​, reports on the therapeutic mechanism of inobrodib and relevant clinical results. The paper demonstrates inobrodib’s action as a potent and selective inhibitor of the bromodomains of p300 and CBP and shows how it has a profound impact on the regulatory elements which control expression of key cancer driver genes. Inobrodib induces a significant redistribution of p300/CBP away from sites occupied by oncogenic master transcription factors. This novel approach is distinct from other oral agents such as the IMiD and CELMoD class of drugs.  The data show that this mechanism of action is synergistic with a number of existing developmental agents. Well-tolerated new type of treatment Somervaille said: “We are pleased to share how targeting the bromodomain of p300/CBP can deliver a new way to treat specific blood cancers. The mechanism of action is more targeted than might be anticipated, offering clear potential to be a well-tolerated new type of treatment.” The paper also describes initial data from a phase 1a/2b hematological malignancy clinical trial. Inobrodib can be well tolerated whilst demonstrating potential in treating relapsed refractory multiple myeloma and AML. It is an oral drug, a capsule taken twice daily.  A key patient preference is for treatments that are easy to administer and can be taken in community settings.  This also reduces the overall healthcare burden. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Emma Searle, consultant haematologist at The Christie NHS Foundation Trust, who has overseen the care of many of the patients on the clinical trial, said: “Early clinical data shows promising tolerability, a key factor in treating patients with relapsed, refractory multiple myeloma who have exhausted standard-of-care therapies.  We look forward to sharing efficacy data at ASH in December.” Hematological malignancies Leif Bergsagel, is professor of medicine for the Mayo Clinic College of Medicine, and a consultant in the division of hematology and medical oncology, department of internal medicine, at Mayo Clinic in Arizona. He said: “This new paper supports that targeting p300/CBP to treat hematological malignancies is showing increasing potential.  It is clearly a distinctly new approach beyond the existing standard of care therapies and others in late-stage development.” CellCentric’s ongoing blood cancer trial ​ involves patients with a range of hematological malignancies, including in relapsed/refractory multiple myeloma. Good safety profile Inobrodib is a new type of treatment for people with cancer. Delivered as an oral capsule, CellCentric says it is easy for patients to take and can be used at home without the need for intensive monitoring. As it has a good safety profile for a drug in this setting, it may be used by those who are unable to tolerate other treatments, including the elderly and frail. The company added that this potentially represents a significant benefit over existing treatment options as it enables a wider range of patients to be treated, including those who want to be treated closer to home. Being an oral capsule, it has the potential to present a lower overall burden on the healthcare system as compared to more complex therapies, such as cell-based therapies. In June 2023, CellCentric was granted orphan drug and fast track designation status from the FDA for inobrodib. Further clinical data will be announced at the American Society for Hematology annual meeting (ASH), San Diego 9-12 December 2023.