更新于：2024-06-21
BLU-222
更新于：2024-06-21
概要
基本信息
非在研机构- |
最高研发阶段临床1/2期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评- |
关联
1
项与 BLU-222 相关的临床试验A Phase 1/2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of BLU-222 as a Single Agent and in Combination Therapy for Patients With Advanced Solid Tumors
This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of BLU-222, a selective inhibitor of CDK2.
开始日期2022-04-07 |
申办/合作机构 |
100 项与 BLU-222 相关的临床结果
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100 项与 BLU-222 相关的转化医学
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100 项与 BLU-222 相关的专利（医药）
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1
项与 BLU-222 相关的文献（医药）2011-01-01·Bioscience trends4区 · 生物学
Osteogenic differentiation of human ligament fibroblasts induced by conditioned medium of osteoclast-like cells
4区 · 生物学
Article
作者: Han, Jinxiang ; Yu, Fangcang ; Zhang, Xiume ; Zhou, Xiaoyan ; Cui, Yazhou
Osteoclasts secrete factors that may promote mesenchymal stem cell mineralization in vitro. Fibroblasts are the most common cells in connective tissue and are involved in the process of exotic ossification in many diseases such as ankylosing spondylitis. The purpose of this study was to investigate whether osteoclast-like cells would induce the osteogenic differentiation of fibroblasts in vitro. In the present study, osteoclast-like cells (OLCs) were generated by CD14(+) cells from human peripheral blood. Fibroblasts were primarily cultured from spinal ligaments. After treatment with conditioned medium of OLCs, the level of alkaline phosphatase (ALP) and mineralization of fibroblasts increased significantly. cDNA microarray analysis identified a set of differentially expressed mRNA associated with signal transduction, cell differentiation, and bone formation, and microarray analysis of microRNA expression profiles revealed a group of microRNAs, including hsa-miR-20a, hsa-miR-300, hsa-miR-185, hsa-miR-30d, hsa-miR-320a, hsamiR- 130b, hsa-miR-33a, hsa-miR-155, and hsa-miR-222, that were significantly downregulated. These microRNAs were predicted to have an inhibitory effect on genes associated with osteogenic differentiation, such as BMP2, Osteocalcin, and Runx2. The current results suggest that osteoclasts might induce the osteogenic differentiation of fibroblasts in vitro and that miRNA may play an important role in regulation of the cell-cell interaction between osteoclasts and fibroblasts.
36
项与 BLU-222 相关的新闻（医药）2024-05-23
-- Updated Phase 1 dose escalation data show that BLU-222 in combination with ribociclib and fulvestrant was well-tolerated at clinically active dose levels with no dose-limiting toxicities --
-- Early signal of clinical activity includes compelling biomarker reductions correlated with BLU-222 exposure --
CAMBRIDGE, Mass., May 23, 2024 /PRNewswire/ -- Blueprint Medicines Corporation (Nasdaq: BPMC) today announced updated data from the ongoing Phase 1 dose escalation portion of the VELA clinical trial of BLU-222, an investigational, highly selective and potent CDK2 inhibitor, in combination with ribociclib and fulvestrant in patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The data, which mark the first promising clinical results for a CDK2 inhibitor in combination with an approved CDK4/6 inhibitor, will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting on June 2, 2024.
"At ASCO, we will present highly encouraging clinical data showing that our selective CDK2 inhibitor BLU-222, in combination with ribociclib, a standard of care CDK4/6 inhibitor for HR+ breast cancer, is very well-tolerated and delivers early evidence of clinical activity. This represents a highly significant milestone and holds promise as an important new cornerstone for the treatment of breast cancer, including in the front-line metastatic setting," said Becker Hewes, M.D., Chief Medical Officer at Blueprint Medicines. "These data validate the potency and selectivity of BLU-222, its potential as a first- and best-in-class CDK2 inhibitor, and its use as the combination partner of choice in breast cancer. With these data in hand, we are advancing ongoing partnering discussions that aim to accelerate development of BLU-222 into registration-directed clinical trials."
Updated Phase 1/2 VELA Trial Results
Based on previously reported positive BLU-222 monotherapy clinical data, a combination dose escalation arm was initiated in the VELA trial to assess the safety and clinical activity of BLU-222 in combination with ribociclib, a CDK4/6 inhibitor approved by the U.S. Food and Drug Administration for advanced or metastatic HR+/HER2- breast cancer, and fulvestrant, a commonly used estrogen receptor antagonist. As of the data cutoff date, 19 patients with HR+/HER2- breast cancer who had progressed on prior CDK4/6 inhibitors were treated with 100 mg to 400 mg twice daily (BID) of BLU-222 plus 400 mg once daily (QD) of ribociclib and combined with fulvestrant.
The combination of BLU-222, ribociclib, and fulvestrant was well-tolerated at all BLU-222 dose levels tested. No dose-limiting toxicities, treatment-related severe adverse events (SAEs), or BLU-222-related treatment discontinuations were reported. Treatment-related hematologic and gastrointestinal AEs were generally mild. The maximum tolerated combination dose has not been identified, and combination dose escalation is ongoing.
Pharmacokinetic data showed dose-proportional exposures of BLU-222, with sustained coverage above the predicted efficacious concentration at the 400 mg BID dose level. In addition, the combination of BLU-222 with ribociclib and fulvestrant had no clinically meaningful impact on individual drug exposures.
Preliminary clinical activity showed compelling reductions in thymidine kinase 1 (TK1) and circulating tumor DNA (ctDNA), biomarkers that have been shown to be predictive of clinical benefit. TK1, a biomarker of tumor proliferation, had the deepest reduction among patients treated with BLU-222 400 mg BID, ribociclib 400 mg QD, and combined with fulvestrant, and was statistically significantly correlated with BLU-222 exposure. All patients with evaluable ctDNA, a biomarker of tumor burden, treated with the BLU-222 400 mg BID combination dose regimen showed ctDNA reductions. Early evidence of clinical benefit includes an unconfirmed partial response in a patient who had previously progressed following six lines of therapy in the metastatic setting, including prior palbociclib and trastuzumab deruxtecan. These data highlight the impact of CDK2 inhibition when BLU-222 is combined with other therapies.
Detailed data will be presented by Dr. Dejan Duric from the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital on June 2, 2024, during the "Breast Cancer – Metastatic" poster session at 9:00 a.m. CT. At the time of presentation, a copy of the poster will be available in the "Science—Publications and Presentations" section of the company's website at .
About BLU-222
BLU-222 is a highly selective and potent investigational CDK2 inhibitor with first- and best-in-class potential, designed by scientists at Blueprint Medicines. CDK2 is a cell cycle regulator and an important cancer target, with relevance in HR+/HER2- breast cancer and other malignancies, such as subsets of ovarian and endometrial cancer. Across multiple cancer types, aberrant CCNE1 hyperactivates CDK2, resulting in cell cycle dysregulation and tumor proliferation. Aberrant CCNE1 has been observed as a primary driver of disease, as well as a mechanism of resistance to CDK4/6 inhibitors. In HR+/HER2- breast cancer, the advent of CDK4/6 inhibitors has improved treatment; however, disease progression is nearly universal, and new innovation is needed to improve outcomes and prolong clinical benefit. Historically, CDK2 inhibitor development by others has been challenged due to poor selectivity limiting tolerability and combination potential. Beyond BLU-222, Blueprint Medicines is advancing additional preclinical therapeutic candidates for cell cycle targets including BLU-956, a next-generation CDK2 inhibitor, a CDK2 targeted protein degradation program, and an additional undisclosed research program.
About Blueprint Medicines
Blueprint Medicines is a global, fully integrated biopharmaceutical company that invents life-changing medicines. We seek to alleviate human suffering by solving important medical problems in two core focus areas: allergy/inflammation and oncology/hematology. Our approach begins by targeting the root causes of disease, using deep scientific knowledge in our core focus areas and drug discovery expertise across multiple therapeutic modalities. We have a track record of success with two approved medicines, including AYVAKIT®/AYVAKYT® (avapritinib) which we are bringing to patients with systemic mastocytosis (SM) in the U.S. and Europe. Leveraging our established research, development, and commercial capability and infrastructure, we now aim to significantly scale our impact by advancing a broad pipeline of programs ranging from early science to advanced clinical trials in mast cell diseases including SM and chronic urticaria, breast cancer and other solid tumors. For more information, visit and follow us on X (formerly Twitter; @BlueprintMeds) and LinkedIn.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation: statements regarding plans, strategies, timelines and expectations for Blueprint Medicines' operations, including its expectations for our current or future approved drugs and drug candidates, including BLU-222; the development of BLU-222 and whether it has first-and best-in-class potential; the potential benefits of any of our current or future approved drugs or drug candidates in treating patients, including the potential benefits of BLU-222 in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer; and the potential to partner with a third party to accelerate development of BLU-222 into registration-directed clinical trials. The words "aim," "may," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "estimate," "predict," "project," "potential," "continue," "target" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks and uncertainties related to: the delay of any current or planned clinical trials or the development of the company's current or future drug candidates; the company's ability to successfully demonstrate the safety and efficacy of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; the possibility that preclinical and clinical results for the company's drug candidates may not support further development of such drug candidates either as monotherapies or in combination with other agents or may impact the anticipated timing of data or regulatory submissions; the timing of the initiation of clinical trials and trial cohorts at clinical trial sites and the possibility patient enrollment rates may be delayed or slower than anticipated; the actions of regulatory agencies and how this may affect the initiation, timing and progress of clinical trials; the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its products and current or future drug candidates it is developing; and the success of the company's current and future collaborations, partnerships or licensing arrangements. Any forward-looking statements contained in this press release represent the company's views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law, the company explicitly disclaims any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements.
Trademarks
Blueprint Medicines and associated logos are trademarks of Blueprint Medicines Corporation.
SOURCE Blueprint Medicines Corporation
临床1期临床结果ASCO会议上市批准
2024-05-02
-- Achieved $92.5 million in AYVAKIT net product revenues in the first quarter 2024 --
-- Raising guidance to $390 million to $410 million in full year AYVAKIT net product revenues --
-- Strengthening presence in allergy and inflammation with the IND for wild-type KIT inhibitor BLU-808 on track for filing in Q2 --
CAMBRIDGE, Mass., May 2, 2024 /PRNewswire/ -- Blueprint Medicines Corporation (Nasdaq: BPMC) today reported financial results, provided a business update for the first quarter ended March 31, 2024, and provided updated financial guidance.
"We delivered another very strong quarter in our launch of AYVAKIT in indolent systemic mastocytosis (ISM) and have entered 2024 in a position of strength with great momentum across all aspects of our business. The first few quarters of a launch are critical in defining the sales trajectory for a product, and our revenue to-date positions us squarely on the path to achieve more than $2 billion in peak sales for AYVAKIT in systemic mastocytosis," said Kate Haviland, Chief Executive Officer of Blueprint Medicines. "Importantly, our growing revenue also enables us to invest in additional, compelling opportunities across our pipeline, where we can drive longer-term growth. This includes advancing our portfolio focused in allergy and inflammation as we move BLU-808 into the clinic in the second half of this year. I am proud of our team's strong operational execution against our core value drivers, which enables Blueprint to realize the harmony between our mission of bringing new, innovative medicines to patients and building a robust and thriving business that will create substantial value for our shareholders."
First Quarter 2024 Highlights and Recent Progress
Mast cell disorders
Achieved AYVAKIT net product revenues of $92.5 million for first quarter of 2024, representing more than 135 percent growth year-over-year.
Presented long-term data from the PIONEER trial of AYVAKIT in ISM, demonstrating durable symptom impact and a well-tolerated safety profile, supporting long-term treatment and consistent with real-world experience observed in the commercial setting. Read the presentation here.
Presented preclinical data for BLU-808, a highly selective and potent investigational oral wild-type KIT inhibitor with best-in-class potential, for chronic urticaria and other mast cell disorders. BLU-808 treatment led to dose-dependent inhibition and depletion of mast cells in multiple in vivo studies, and also improved lung function in an ovalbumin-induced asthma model. Based on these data, Blueprint is on track to submit an investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA) for BLU-808 in the second quarter of 2024 to enable the initiation of a Phase 1 study in healthy volunteers. Read the presentation here.
Highlighted Blueprint's strategy to leverage the company's proven expertise in developing mast cell-targeted therapies to address large medical needs in allergy and inflammation. The company plans to host additional educational webcasts highlighting the evolving science around Blueprint's portfolio strategy in the future. Watch the replay here.
HR+/HER2- breast cancer
Advanced the development of BLU-222, an oral, potent, and selective CDK2 inhibitor in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer, with plans to present the first positive combination safety data with signal of early clinical activity for a CDK2 inhibitor in combination with an approved CDK4/6 inhibitor at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.
Corporate
Announced that Rigel Pharmaceuticals, Inc. is purchasing the U.S. rights to research, develop, manufacture, and commercialize GAVRETO® (pralsetinib), which allows continuity of patient access to GAVRETO in the U.S.
Published third annual Sustainability Report, highlighting Blueprint's 2023 progress on environmental, social, and governance (ESG) initiatives and strategy and reflecting the results of a materiality assessment to focus our strategy on the most important ESG topics for the company and shareholders. Read the report here.
2024 Financial Guidance
Blueprint Medicines now anticipates approximately $390 million to $410 million in global AYVAKIT net product revenues for all approved indications in 2024, an increase from the previous range of $360 million to $390 million. This updated guidance reflects continued execution in the global launch for ISM, as well as a stronger than anticipated first quarter. The company continues to expect that full-year operating expenses and cash burn will decline in 2024 as compared to 2023, and that its existing cash, cash equivalents and investments, together with anticipated future product revenues, will enable the company to maintain a durable capital position to achieve a self-sustainable financial profile.
Key Upcoming Milestones
The company plans to achieve the following remaining milestones in the first half of 2024:
Mast cell disorders
Submit an IND to FDA for BLU-808 in the second quarter of 2024 to enable the initiation of a Phase 1 study in healthy volunteers.
HR+/HER2- breast cancer
Present data for BLU-222 in combination with ribociclib and fulvestrant for HR+/HER2- breast cancer at the 2024 ASCO Annual Meeting.
Continue ongoing strategic business development discussions.
First Quarter 2024 Results
Revenues: Revenues were $96.1 million for the first quarter of 2024, including $92.5 million of net product revenues from sales of AYVAKIT/AYVAKYT and $3.6 million in collaboration revenues. Blueprint Medicines recorded revenues of $63.3 million in the first quarter of 2023, including $39.1 million of net product revenues from sales of AYVAKIT/AYVAKIT and $24.2 million in collaboration revenues.
Cost of Sales: Cost of sales was $3.2 million for the first quarter of 2024, as compared to $3.2 million for the first quarter of 2023. The relatively flat cost of sales was primarily attributed to the increased sales of lower cost dosages of AYVAKIT/AYVAKIT.
R&D Expenses: Research and development expenses were $88.2 million for the first quarter of 2024, as compared to $112.1 million for the first quarter of 2023. This decrease was primarily due to operational efficiency across our portfolio as we execute across our top priority programs and the timing of manufacturing of clinical trial materials. Research and development expenses included $10.9 million in stock-based compensation expenses for the first quarter of 2024.
SG&A Expenses: Selling, general and administrative expenses were $83.6 million for the first quarter of 2024, as compared to $71.0 million for the first quarter of 2023. This increase was primarily due to an increase in activities related to the commercialization of AYVAKIT/AYVAKYT. Selling, general, and administrative expenses included $13.4 million in stock-based compensation expenses for the first quarter of 2024.
Net Income (Loss): Net income was $89.1 million for the first quarter of 2024, as compared to a net loss of $129.6 million for the first quarter of 2023. The net income was primarily driven by a one-time non-cash debt extinguishment gain of $173.7 million recorded in connection with the Royalty Pharma termination agreement in the first quarter of 2024.
Cash Position: As of March 31, 2024, cash, cash equivalents and investments were $735.6 million, as compared to $767.2 million as of December 31, 2023. Blueprint Medicine's cash and investments provide a durable capital position which enables the company to reach a self-sustainable profile.
Conference Call Information
Blueprint Medicines will host a live conference call and webcast at 8:00 a.m. ET today to discuss first quarter 2024 financial results and recent business activities. The conference call may be accessed by dialing 833-470-1428 (domestic) or 404-975-4839 (international), and referring to conference ID 186292. A webcast of the call will also be available under "Events and Presentations" in the Investors & Media section of the Blueprint Medicines website at . The archived webcast will be available on Blueprint Medicines' website approximately two hours after the conference call and will be available for 30 days following the call.
Upcoming Investor Conferences
Blueprint Medicines will participate in two upcoming investor conferences:
Citizens JMP Life Sciences Conference on Monday, May 13, 2024 at 10:00 am ET.
Goldman Sachs 45th Annual Global Healthcare Conference on Monday, June 10, 2024 at 10:40 am ET.
A live webcast of the fireside discussions will be available under "Events and Presentations" in the Investors & Media section of the Blueprint Medicines website at . A replay of the webcasts will be archived on the Blueprint Medicines website for 30 days following the events.
About Blueprint Medicines
Blueprint Medicines is a global, fully integrated biopharmaceutical company that invents life-changing medicines. We seek to alleviate human suffering by solving important medical problems in two core focus areas: allergy/inflammation and oncology/hematology. Our approach begins by targeting the root causes of disease, using deep scientific knowledge in our core focus areas and drug discovery expertise across multiple therapeutic modalities. We have a track record of success with two approved medicines, including AYVAKIT®/AYVAKYT® (avapritinib) which we are bringing to patients with systemic mastocytosis (SM) in the U.S. and Europe. Leveraging our established research, development, and commercial capability and infrastructure, we now aim to significantly scale our impact by advancing a broad pipeline of programs ranging from early science to advanced clinical trials in mast cell diseases including SM and chronic urticaria, breast cancer and other solid tumors. For more information, visit and follow us on X (formerly Twitter; @BlueprintMeds) and LinkedIn.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans, strategies, timelines and expectations for Blueprint Medicines' operations, including its expectations for growth in 2024; statements regarding our current or future approved drugs and drug candidates and operations, including AYVAKIT's potential as a greater than $2 billion product, plans to advance our portfolio by targeting additional allergic-inflammatory diseases driven by mast cells, plans to submit an investigational new drug application for BLU-808 and present combination dose escalation data for BLU-222 in combination with ribociclib and fulvestrant in patients HR+/HER2- breast cancer at ASCO; expectations related to the markets for our current or future approved drugs and drug candidates; the potential benefits of any of our current or future approved drugs or drug candidates in treating patients; and our financial performance, strategy, goals and anticipated milestones, business plans and focus, including expectations regarding our revenue ramp, continued decline in operating expenses and cash burn and potential profitability. The words "aim," "may," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "estimate," "predict," "project," "potential," "continue," "target" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation: the risk of delay of any current or planned clinical trials or the development of Blueprint Medicines' current or future drug candidates; risks related to Blueprint Medicines' ability to successfully demonstrate the safety and efficacy of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; preclinical and clinical results for Blueprint Medicines' drug candidates may not support further development of such drug candidates either as monotherapies or in combination with other agents or may impact the anticipated timing of data or regulatory submissions; the timing of the initiation of clinical trials and trial cohorts at clinical trial sites and patient enrollment rates may be delayed or slower than anticipated; actions of regulatory agencies may affect the initiation, timing and progress of clinical trials; risks related to Blueprint Medicines' ability to obtain, maintain and enforce patent and other intellectual property protection for its products and current or future drug candidates it is developing; the success of Blueprint Medicines' current and future collaborations, financing arrangements, partnerships or licensing arrangements; and the accuracy of our estimates of revenues, expenses and capital requirements. Any forward-looking statements contained in this press release represent Blueprint Medicines' views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law, Blueprint Medicines explicitly disclaims any obligation to update any forward-looking statements.
Trademarks
Blueprint Medicines, AYVAKIT, AYVAKYT and associated logos are trademarks of Blueprint Medicines Corporation. GAVRETO and associated logos are trademarks of Blueprint Medicines Corporation outside of the United States.
SOURCE Blueprint Medicines Corporation
财报临床1期
2024-03-30
·医药观澜
▎药明康德内容团队编辑近日，在美国化学会（ACS）2024春季会议的“首次公开（First-time disclosures）”环节中，六家生物医药公司首次披露了他们正在研发中的抗肿瘤小分子药物的化学结构和初期临床试验数据。这些潜在的新药针对的靶点包括免疫检查点蛋白和多个与癌症进展密切相关的关键酶，这些靶点由于多种原因难于靶向。这六款小分子的结构设计和作用机制上呈现出创新性，也展现了业界在攻克难于靶向蛋白靶点时的多种解决方案。药明康德内容团队将依据ACS旗下C&EN网站的报道及公开信息，向读者详细介绍这些创新分子结构及其相应的临床进展。候选药物：ORIC-533研发机构：Oric Pharmaceuticals靶点：CD73疾病领域：多发性骨髓瘤▲ORIC-533的结构式（图片来源：参考资料[1]）ORIC-533是一种抑制腺苷生成过程中的关键酶CD73的口服候选药物。CD73是一种控制细胞外腺苷产生速率的酶，它的过度活跃与多种癌症的不良预后有关。该酶是免疫抑制途径的一部分，与多发性骨髓瘤和其他癌症的耐药性相关。开发这类药物的挑战在于，即使在高浓度的单磷酸腺苷（CD73的常规底物）竞争性地与CD73结合的情况下，开发的药物分子仍能保持药效。ORIC-533分子的核心是腺苷衍生物，研究人员通过增强氢键形成并且同时平衡整体电荷和极性，以保持较高的生物利用度。他们发现，膦酸酯基团周围的区域对于在生化试验中阻断腺苷产生的效果影响最大，该基团在蛋白质和锌离子之间形成盐桥。此外，通过醚键连接的四唑与CD73活性位点中的三个关键氨基酸形成氢键，从而增强了候选药物的功效。目前，ORIC-533正在针对多发性骨髓瘤患者开展1b期临床试验，它是三种正处于临床试验阶段的CD73小分子抑制剂之一。初步的临床试验数据显示，ORIC-533具有良好的药代动力学特征，对可溶性CD73酶活性具有强效的抑制作用，显示出了良好的靶向作用。该药物总体耐受性良好，主要观察到的治疗相关不良事件为1级和2级，没有发现任何特定的复发性毒性、剂量限制性毒性、剂量减少的情况或与治疗相关的严重不良事件。目前，Oric Pharmaceuticals正计划与辉瑞（Pfizer）合作开展2期临床研究。候选药物：NX-1607研发机构：Nurix Therapeutics靶点：CBL-B（Casitas B细胞淋巴瘤蛋白B）疾病领域：癌症▲NX-1607的结构式（图片来源：参考资料[1]）Nurix Therapeutics开发的NX-1607是一种靶向CBL-B的创新免疫疗法。CBL-B作为一种E3泛素连接酶，在多种免疫细胞中发挥作用，通过促进关键下游信号蛋白（如Vav1，PLCγ）的泛素化和降解，对免疫功能进行负向调节。在CBLB基因敲除的小鼠模型中，观察到了对移植肿瘤的抵抗性，展示了CBL-B作为一种新型细胞内免疫检查点的潜力。然而，由于CBL-B缺乏明确的小分子对接位点，使其成为一个具有挑战性的药物靶点。NX-1607的独特之处在于其作为一种分子胶，能够与CBL-B结合并促使其与不同亚基结合，从而将CBL-B锁定在非活性构象中，阻止其向活性状态转换。这种机制有效地抑制了CBL-B的功能。通过高通量筛选技术，研究团队发现，将N-甲基三唑结构引入至候选分子中，能够有效地填补蛋白质的结合口袋，其中三唑的硝基通过氢键与蛋白质形成稳定结合，延长了分子与蛋白的结合时间。环丁烷基团作为间隔结构（spacer），有助于确保三唑以正确的角度进入结合口袋，而一个苄胺基团则插入到蛋白的另一个关键疏水口袋结构中。在临床前研究中，NX-1607显著提升了T细胞的活性，并在单药治疗以及与抗PD-1免疫检查点抑制剂联合使用时展现出抗肿瘤效果。得益于其良好的溶解性和高渗透性，NX-1607的生产过程相对简便。目前，针对晚期实体瘤患者的NX-1607单药以及与紫杉醇联合使用的1期临床试验正在进行中。候选药物：SGR-1505研发机构：Schrödinger靶点：MALT1疾病领域：B细胞淋巴瘤▲SGR-1505的结构式（图片来源：参考资料[1]）SGR-1505是Schrödinger公司利用其专有基于物理原理的计算平台发现的一种MALT1蛋白靶向疗法。该疗法的设计理念是通过与MALT1蛋白的一个变构位点结合，从而使癌细胞中的MALT1蛋白失活。MALT1是一种位于布鲁顿氏酪氨酸激酶（BTK）下游信号的蛋白酶，是多种非霍奇金B细胞淋巴瘤的潜在治疗靶点。对于那些对现有BTK抑制剂产生抗药性的癌症病患，MALT1提供了一个有希望的备选靶点。利用高级计算模型预测蛋白质与小分子之间的相互作用，Schrödinger公司能够从数千个候选结构中筛选出最具潜力的候选物，并将其送入实验室进行制造和测试。这一药物开发过程耗时约10个月，经过对超过80亿个化合物的计算评估，最终选出了129种分子进行合成。目前，SGR-1505正在晚期B细胞淋巴瘤患者中进行1期临床试验。Schrödinger的研究团队预计，初步数据将于2024年底或2025年公布，届时将为B细胞淋巴瘤的治疗提供新的见解。候选药物：DCC-3116研发机构：Deciphera Pharmaceuticals靶点：ULK1/2疾病领域：与RAS/RAF基因突变有关的癌症▲DCC-3116的结构式（图片来源：参考资料[1]）在许多癌症类型中，受体酪氨酸激酶（RTK）通路的突变非常普遍，因此，针对RTK蛋白的治疗手段不断涌现。但癌细胞能通过启动自噬来抵御这些治疗手段，自噬通过回收和再利用损坏的蛋白质帮助癌细胞存活。ULK1和ULK2蛋白是自噬过程的关键组分，Deciphera公司的研究团队正致力于开发一种抑制这两种蛋白的药物，旨在阻断癌细胞的自噬过程。DCC-3116是Deciphera公司开发的一款选择性的小分子ULK1/2激酶抑制剂，旨在通过抑制负责启动自噬的ULK1/2激酶来抑制癌症自噬，从而影响肿瘤细胞的存活。它拥有一个中央嘧啶基团，并携带两个仲胺基团形成的双臂结构，这使得它能与目标蛋白结合并将其锁定在非活性构象中。DCC-3116与其他具有相似结构的候选药物相比，具有更高的药效和更缓慢的解离速度。这一特性归因于其分子结构中的两臂与蛋白质之间的优化相互作用：甲基哌嗪与蛋白中的关键天冬氨酸残基发生相互作用，同时，内酰胺环恰好适配于酶的P环形成的口袋结构。在动物模型中，DCC-3116展现了有效的自噬抑制和抗肿瘤活性。基于这些前期成果，Deciphera公司目前正在进行DCC-3116的单药治疗以及与RTK抑制剂联合使用的1期临床试验。Deciphera公司希望在今年晚些时候能够确定用于2期临床试验的给药剂量。候选药物：TNG348研发机构：Tango Therapeutics靶点：USP1疾病领域：BRCA1/2突变癌症和其他同源重组缺陷（HRD+）癌症▲TNG348的结构式（图片来源：参考资料[1]）TNG348是一种针对USP1的可逆变构抑制剂，被认为是治疗HRD+癌症的潜在药物。在HRD+癌症中，DNA修复机制遭到破坏，Tango公司的研究团队提出，抑制DNA修复酶USP1是消灭这类癌细胞的一种有效策略。USP1是一种去泛素化酶，对于BRCA1/2突变和其他HRD+癌细胞的生存和增殖至关重要。在BRCA1/2突变的情况下，通过抑制USP1可以诱导所谓的“合成致死”。正常细胞有多种机制来修复受损DNA并防止细胞死亡，而BRCA1/2突变细胞则依赖于转座子合成和碱基切除修复。抑制USP1会影响转座子合成，从而阻碍DNA复制，导致BRCA1/2突变癌细胞死亡。根据既往有关USP1抑制剂的文献报道，Tango公司的研发团队确定胍衍生物是一条很有前景的候选路径。通过筛选多种苄基连接子和芳香基团上的官能团，研究团队进一步优化了分子结构。为了降低分子核心的碱性并减少对心脏钾通道的潜在不良作用，他们在候选分子上引入了氟化基团。当TNG348与USP1的变构位点结合时，会破坏酶内的氢键网络，从而抑制其活性。临床前研究结果表明，TNG348单独使用或是与PARP抑制剂一起使用都能有效缩小肿瘤。目前，TNG348针对HRD+乳腺癌和卵巢癌患者的1期临床试验已正式启动，去年年底已对首位受试者进行了给药。候选药物：BLU-222研发机构：Blueprint Medicines靶点：细胞周期蛋白依赖性激酶2（CDK2）疾病领域：激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2-）乳腺癌和其他CCNE1变异癌症▲BLU-222的结构式（图片来源：参考资料[1]）CDK是细胞分裂周期的关键调节因素。其中，CDK2是一种非常有前景的药物靶点，尤其是在那些Cyclin E1蛋白过度表达的癌症中，包括对CDK4/6抑制剂耐药的HR+/HER2-乳腺癌。Blueprint公司的研发团队专注于开发针对CDK2的特异性抑制剂，这一过程颇具挑战性，因为CDK2的活性位点与CDK1极为相似。BLU-222是Blueprint公司开发的CDK2特异性抑制剂。Blueprint公司的科研人员充分筛选了公司的化合物库，这个库详细记录了每种化合物与所有人类激酶的相互作用情况，以筛选出特异性的CDK2先导化合物。结果表明，含有吡嗪核心的化合物提供了最佳的选择性和活性组合。带有二氟甲氧基基团的吡唑环能与“门控开关（gatekeeper）”苯基丙氨酸残基中的π电子产生关键的相互作用，从而进一步提高了其对其他激酶的选择性。这些努力最终促成了BLU-222分子的诞生，该分子对CDK2的选择性比对CDK1高出90倍。目前，BLU-222正在进行1期临床试验，不仅作为单药治疗方案，也在与CDK4/6抑制剂的联合用药方案中进行测试。随着2024年美国化学学会春季大会的成功闭幕，一批候选抗癌药物的亮相标志着产业界在抗癌领域取得了更进一步的进展。期待与这些候选新药能够获得深入研究和进一步验证，在不远的将来为癌症患者提供更为优化和有效的治疗选择。参考资料：[1] Structures of new cancer drug candidates revealed，Retrieved March 25, 2024, from https://cen-acs-org.libproxy1.nus.edu.sg/acs-news/acs-meeting-news/Structures-new-cancer-drug-candidates/102/web/2024/03本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转发授权请在「药明康德」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。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。
免疫疗法临床2期临床1期
100 项与 BLU-222 相关的药物交易
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 食管腺癌 | 临床2期 | 美国 | 2022-04-07 | |
| 食管腺癌 | 临床2期 | 意大利 | 2022-04-07 | |
| 食管腺癌 | 临床2期 | 英国 | 2022-04-07 | |
| 晚期恶性实体瘤 | 临床2期 | 美国 | 2022-04-07 | |
| 晚期恶性实体瘤 | 临床2期 | 意大利 | 2022-04-07 | |
| 晚期恶性实体瘤 | 临床2期 | 英国 | 2022-04-07 | |
| 癌肉瘤 | 临床2期 | 美国 | 2022-04-07 | |
| 癌肉瘤 | 临床2期 | 意大利 | 2022-04-07 | |
| 癌肉瘤 | 临床2期 | 英国 | 2022-04-07 | |
| 子宫内膜癌 | 临床2期 | 美国 | 2022-04-07 |
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| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床1/2期 | 64 | 鬱淵觸餘餘鏇糧鬱鬱憲(襯顧選築鏇網繭鹽繭鏇) = 糧觸淵顧選顧獵鑰壓築 願鏇鬱範繭窪廠窪積積 (蓋壓網膚顧願鬱網製構 ) | 积极 | 2024-05-24 | |||
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临床1期 | 27 | 顧鹽選遞襯鹽淵膚觸壓(觸夢繭遞齋衊範獵築鑰) = nausea 33%, vomiting 22%, anemia 22%, diarrhea 22%, and fatigue 18%. 鹽鑰獵簾衊獵衊廠餘鏇 (鬱鏇衊憲憲獵鏇壓鏇淵 ) 更多 | 积极 | 2023-05-26 |
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