A Phase 1/2, Open-label, Multicenter Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of CC-90011 in Combination With Venetoclax and Azacitidine in R/R Acute Myeloid Leukemia (AML) and Treatment-naïve Subjects With AML Who Are Not Eligible for Intensive Induction Chemotherapy

CC-90011-AML-002 is a Phase 1/2, open-label, multicenter study to assess the safety, tolerability, and preliminary efficacy of CC-90011 given concurrently with Venetoclax and Azacitidine. This study will include 3 parts: a dose escalation part in R/R AML, a dose escalation part in ndAML (treatment-naïve participants with AML who are ≥ 75 years of age or are ≥ 18 to 74 years of age and otherwise not eligible for intensive induction chemotherapy), and a randomized dose expansion part in ndAML of Venetoclax and Azacitidine with or without CC-90011.

开始日期2021-10-14

申办/合作机构

Celgene Corp.

NCT04628988 / Completed临床1期

A Phase 1, Open-label, Functional Imaging Study to Assess Whether CC-90011 Reverses the Castration Resistance Due to Lineage Switch in Subjects With Metastatic Castration-resistant Prostate Cancer (mCRPC) Who Have Failed Enzalutamide as Last Prior Therapy, Followed by a Dose Finding Study of CC-90011 Combined With Abiraterone and Prednisone

This is an open-label, positron emission tomography (PET) imaging Proof of Biology (POB) study to determine whether CC -90011 reverses, by the induction of androgen receptor (AR) expression, the castration resistance, due to lineage switch, in participants with mCRPC that have failed enzalutamide as last prior therapy. This study aims to assess whether CC-90011 can induce AR expression and, consequently, re-sensitize tumors to anti-hormonal therapy.

开始日期2021-07-28

申办/合作机构

Celgene Corp.

NCT04350463 / Completed临床2期

A Phase 2, Multicenter, Open-label, Multi-cohort Study to Assess Safety and Efficacy of CC-90011 in Combination With Nivolumab in Subjects With Advanced Cancers

This is a Phase 2, multicenter, open-label, multi-cohort study to assess safety and efficacy of CC-90011 in combination with nivolumab in subjects with small cell lung cancer or squamous non-small cell lung cancer who have progressed after 1 or 2 lines of therapies.
The primary objectives of the study are to evaluate the overall response rate of subjects treated with CC-90011 in combination with nivolumab in three cohorts:
Cohort A: SCLC in ICI naïve subjects
Cohort B: SCLC in ICI progressor subjects
Cohort C: sqNSCLC in ICI progressor subjects Overall response rate is defined as the proportion of subjects in the treated population who had complete response (CR) or partial response (PR) as assessed by Investigator review per RECIST v1.1.
In Cohort A, expected ORR for nivolumab monotherapy is 14% while target ORR is 30%. To achieve at least 80% power with one-sided type 1 error 0.1, 39 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 12 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 2 or more subjects responding, Cohort A will continue to enroll an additional 27 subjects. If 1 or less subjects respond in stage 1, Cohort A will stop for futility.
In Cohort B and C, expected ORR for nivolumab monotherapy is 5% while target ORR is 15%. To achieve at least 80% power with one-sided type 1 error 0.1, 48 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 14 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 1 or more subjects responding, Cohort B and C will continue to enroll an additional 34 subjects each. If 0 subjects respond in stage 1, Cohort B and C will stop for futility.

开始日期2020-07-14

申办/合作机构

Celgene Corp.

100 项与 Pulrodemstat 相关的临床结果

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100 项与 Pulrodemstat 相关的转化医学

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100 项与 Pulrodemstat 相关的专利（医药）

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项与 Pulrodemstat 相关的文献（医药）

2024-01-25·Journal of medicinal chemistry1区 · 医学

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

1区 · 医学

Review

作者: Wang, Shu-Wu ; Wang, Bo ; Hou, Wen-Qing ; Fu, Meng-Jie ; Ji, Shi-Kun ; Shen, Liang ; Liu, Hong-Min ; Dai, Xing-Jie ; Wang, Shao-Peng

Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.

2024-01-11·The Journal of Physical Chemistry B

Uncovering New Conformational States of the Substrate Binding Pocket of LSD1 Potential for Inhibitor Design via Funnel Metadynamics

Article

作者: Yang, Kecheng ; Liu, Hongmin

Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target for cancer therapy. So far, over 80 crystal structures of LSD1 in different complex states have been deposited in the Protein Data Bank, which are valuable resources for performing structure-based drug design. However, among all of the crystal structures of LSD1, the substrate binding pocket, which is the most efficient druggable site for designing LSD1 inhibitors at present, is very similar no matter whether LSD1 is in the apo or any holo forms, which is inconsistent with its versatile demethylase functions. To investigate whether the substrate binding pocket is rigid or exhibits other representative conformations different from the crystal conformations that are feasible for designing new LSD1 inhibitors, we performed funnel metadynamics simulations to study the conformation dynamics of LSD1 in the binding process of two effective LSD1 inhibitors (CC-90011 and 6X0, CC-90011 undergoing clinical trials). Our results showed that the entrance of the substrate binding pocket is very flexible. Two representative entrance conformations of LSD1 counting against binding with the substrate of histone H3 were detected, which may be used for structure-based LSD1 inhibitor design. Besides, alternative optimal binding modes and prebinding modes for both inhibitors were also detected, which depicted that the key interactions changed along with the binding process. Our results should provide great help for LSD1 inhibitor design.

2023-10-20·ACS chemical biology

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics.

Review

作者: Sahu, Bichismita ; Shinde, Suchita Dattatray ; Baby, Stephin ; Kulkarni, Neeraj

Aberrant expression of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been associated with the incidence of many diseases, particularly cancer, and it has evolved as a promising epigenetic target over the years for treatment. The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat). There is parallel mining for peptide-based LSD1 inhibitors, which exploits the opportunities in the LSD1 substrate binding pocket. This Review highlights the research progress on reversible and irreversible peptide/peptide-derived LSD1 inhibitors. For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors.

项与 Pulrodemstat 相关的新闻（医药）

2022-08-10

·CPhI制药在线

金笔奖 | 靶向LSD1抗肿瘤：药物研发的又一片蓝海

{关注并星标 CPhI制药在线} 肿瘤的发生、发展与遗传物质密切相关。研究表明，即使核苷酸序列没有变化，仍然有可能发生基因表达差异，进而导致疾病的发生。这种调节机制属于表观遗传学范畴，表观遗传学调控主要有DNA甲基化、组蛋白修饰以及微小RNA转录后调控。DNA附着于组蛋白核小体，其转录的开启和关闭受组蛋白修饰状态调节。组蛋白去甲基化酶1（lysine specific demethylase1，LSD1）可以调控组蛋白修饰状态，其表达异常与众多肿瘤疾病的发生和预后有密切关系。一．组蛋白去甲基化酶1（LSD1）与肿瘤组蛋白去甲基化酶1（LSD1），又被称作KDM1A/AOF2，是首个被发现得组蛋白特异性去甲基化酶。LSD1催化黄素腺嘌呤二核苷酸（FAD），属于单胺氧化酶家族。研究显示，LSD1在人、鼠、昆虫和线虫等种属中均有表达，但结构均十分保守。在LSD1被发现之前，组蛋白甲基化修饰长期被认为是不可逆的，直到LSD1被发现，才了解组蛋白甲基化修饰受到组蛋白甲基化酶和去甲基化酶共同调节，保持动态平衡。图一组蛋白去甲基化酶1（LSD1）从结构来看，LSD1包括N端的SWIRM结构域，C端的AOL（胺基氧化酶）结构域和中心定位的Tower结构域。LSD1可以特异性地去除组蛋白H3第4位赖氨酸（H3K4）和第9位赖氨酸（H3K9）的单、二甲基化，从这调节基因转录（包括激活或抑制），相关过程与肿瘤的发生和发展密切相关。现有的研究证实，LSD1可以调控肿瘤基因表达，促进肿瘤细胞的增殖、侵袭和转移。LSD1在肺癌、胃癌、结直肠癌、膀胱癌、食管癌、前列腺癌、肝癌和神经胶质瘤、急性粒细胞白血病等多种癌症疾病中均被发现高表达，且表达程度与癌症分级、恶性程度和预后均有关。二．靶向LSD1的肿瘤治疗策略自LSD1在2004年被发现以来，研究人员就开始了LSD1靶向治疗策略的研究，目前已在LSD1生物学功能研究、抑制剂开发等方面取得了较大进展（图二）。图二 LSD1靶向治疗发展进程当下，开发高效、低毒的高选择性LSD1抑制剂已经成为药物开发领域的热点。LSD1抑制剂按照作用机制可分作两类：不可逆抑制剂和可逆抑制剂。不可逆抑制剂按照结构主要有苯环丙胺类、炔丙基胺类以及苯乙肼类3类，其都是通过与LSD1的辅因子FAD形成加合物从而抑制LSD1的去甲基化作用。目前已有7种苯环丙胺类LSD1不可逆抑制剂获得美国食品药品监督管理局（Food and Drug Administration，FDA）批准进入临床，包括Tranylcypromine、ORY-1001、ORY-2001、GSK-2879552、IMG-7289、INCB059872 和TAK-418（其中，GSK-2879552、INCB059872以及TAK-418的多项临床试验因为安全性、脱靶效应等问题而终止），涉及的癌种包括：急性髓系白血病、小细胞肺癌、骨髓增生异常综合征等。可逆抑制剂方面，LH-1802进入了临床研究准备阶段，CC-90011和SP-2577进入了临床评估阶段。图三 LSD1靶向分子三．代表LSD1抑制剂 1.MAOs相关抑制剂——Tranylcypromine（TCP） LSD1属于单胺氧化酶，其催化区域与MAO-A、MAO-B具有同源性。正因如此，早期开发的LSD1抑制剂多与MAO-A和MAO-B有关。Tranylcypromine（trans-2-phenylcyclopropylamine，TCP），对FAO超家族的单胺氧化酶A（MAO-A）和 B（MAO-B）的抑制活性分别为Ki = 102 μmol·L−1和Ki = 16 μmol·L−1，可抑制5-羟色胺和去甲肾上腺素的分解，从而提高大脑中神经递质水平。该药物在1961年被FDA批准用于治疗深度抑郁症。做为MAOs抑制剂，TCP最早证实可抑制LSD1的催化活性。 TCP对FAO超家族的选择性较差，是一种非特异性的LSD1抑制剂。研究显示，抑制LSD1可以增强视黄酸受体抑制剂全反式维甲酸（all-trans-retinoic acid，ATRA）急性髓系白血病（AML）治疗的敏感性。2014年，马丁路德·哈勒维腾贝格大学发起了一项ATRA与TCP联用的I/II期临床研究（NCT02261779），旨在探讨分析TCP与ATR联用对复发或难治性AML患者的可行性、安全性、有效性。在该研究中，TCP（片剂）10 mg口服/d，ATRA（软胶囊剂）按45 mg·m-2的剂量从第7天开始口服，治疗周期1年。2015年，研发人员一项针对TCP的临床研究（NCT02717884），主要研究TCP对非M3型AML或MDS患者对ATRA致敏性影响的临床I/II期研究。2020年，研究人员又发起了一项评估TCP和ATRA联合治疗复发或难治性AML和MDS的安全性以及耐受性的临床I期研究。临床研究结果显示，LSD1抑制剂TCP可以增强AML细胞对ATRA敏感性，并可能恢复MDS和AML患者对ATRA的敏感性。并且，TCP和ATRA联用显示出了较高的耐受性和安全性。 2.首个进入临床研究的可逆LSD1抑制剂——CC-90011 CC-90011是首个进入临床研究的可逆LSD1抑制剂，其对LSD1的半数抑制浓度IC50 = 0.25 nmol·L−1。2021年，生物制药龙头——新基医药/赛尔基因（Celgene Corporation）针对CC-90011开展了一项Ⅰ/Ⅱ期临床研究（NCT04748848），用于评估CC-90011与AML传统疗法（BCL-2抑制剂维奈托克（venetoclax）和胞嘧啶核苷类似物DNMT抑制剂阿扎胞苷（azacitidine））联用治疗AML的安全性、耐受性和疗效。研究显示，CC-90011与AML传统疗法联用可以抑制与AML发病机制相关的异常LSD1活性，增加AML患者对传统疗法的敏感性。近期，研究人员发起了一项针对CC-90011与广谱抗菌药物利福平（rifampicin）或伊曲康唑（itraconazole）联合用于复发或难治性实体瘤和非霍奇金淋巴瘤的安全性和有效性研究临床实验（NCT02875223）。此外，研究人员针对CC-90011发起了多项目临床研究，包括NCT03850067、NCT04350463、NCT04628988等。已有的临床研究结果显示，CC-90011耐受性好，药代动力学特征优势明显，单用和联用用于肿瘤治疗的前景看好。小结 LSD1做为一个肿瘤药物的新靶点，自被发现以来，迅速成为了医药研究领域的热点。近年来，LSD1抑制剂研究如火如荼，取得了较大的进展，多款药物成功进入临床研究，并表现出了很大的应用前景。目前，虽然尚未有LSD1抑制剂成功上市，但数据已经证明了LSD1是一个优秀的肿瘤治疗靶点，随着研究的不断深入，LSD1必定在肿瘤治疗上大有作为。参考文献： 1.Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021，2022； 2.LSD1 在肿瘤中的研究进展及其抑制剂的开发现状，2020； 3.组蛋白去甲基化酶 LSD1 抑制剂临床研究进展，2022. 作者简介：云天，药物化学博士，主要从事小分子药物研究，尤其擅长小分子药物的合成工艺及后期药物开发研究，已完成多个抗癌药物分子的合成和活性评估。智药研习社8月培训会报名来源：CPhI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPhI制药在线▼点击阅读原文，进入智药研习社~

免疫疗法小分子药物

2022-06-05

·生物制品圈

抗衡罗氏？BMS斥资41亿美元收购Turning Point

为了与罗氏抗衡，加上明年即将上市一款新的癌症药物，BMS将斥资41亿美元收购临床阶段肿瘤学生物制药公司Turning Point Therapeutics。BMS将因此获得Repotrectinib。这是一款用于治疗一线肺癌的潜在药物，目前还处于中期测试阶段，可能会成为罗氏Rozlytrek的竞争对手。BMS将以每股76美元的价格收购Turning Point，总价值为41亿美元。两家公司的董事会已达成一致，预计将于2022年第三季度完成交易。此次收购为BMS的中长期增长添加了动力，也提供了一系列针对导致癌细胞生长常见突变的精准肿瘤药物。明星产品当属先导药物Repotrectinib，这是新一代酪氨酸激酶抑制剂，与Rozlytrek一样，针对ROS1和NTRK基因突变。罗氏的药物Rozlytrek于2019年获批，上市后的第一季度便为这家瑞士制药巨头带来了1600万瑞士法郎（1660万美元）的收入，较上年同期增长了78%。该疗法获批用于一种突变的非小细胞肺癌（NSCLC）、实体瘤，以及ROS1阳性的晚期非小细胞肺癌。在I/II期临床试验中，与现有的ROS1制剂相比，Repotrectinib在治疗一线NSCLC中获得了三项突破性疗法认定，并显示了更长的缓解持续时间。其他涉及Repotrectinib的研究包括晚期成人和儿童实体肿瘤试验，以及早期KRAS靶向联合研究。据BMS称，该疗法预计将于2023年下半年在美国获得批准。BMS还将“挖掘”Turning Point公司其他候选药物的“潜力”，其中包括实体瘤治疗药物Elzovantinib和TPX-0046。Turning Point总裁兼首席执行官Athena Countouriotis博士表示，凭借BMS的商业能力和生产规模，Turning Point可以提高将药物普及患者的速度。BMS首席执行官Giovanni Caforio博士也说道，此次收购保持了公司“战略业务发展的良好记录，进一步提高了我们的增长水平”。SVB Securities分析师认为，这笔交易较Turning Point之前34.16美元的收盘价相比，溢价122%。但上周五下午，收购消息传出后，该公司股价飙升至每股74美元，暴涨116%，总市值近40亿美元。也正如SVB Securities预计的那样，鉴于当前生物技术市场的严峻形势，以及许多公司都在以公司现金或低于现金的价格进行交易的现实，“投资者不会有太大阻力”。该机构预测，Repotrectinib的一线市场潜力为11.4亿美元，二线市场潜力最高可达4.55亿美元。但这可能需要上市后再经过几个季度的时间才能实现，估计要到2024年。Turning Point预计将很快与FDA会面讨论申请事宜，可能会在今年年底前完成这项工作。会议期间，Turning Point有望清楚得知Repotrectinib能否得到加速批准，以及这项疗法是否可以申请“line agnostic”的ROS-1适应症，也就是可以用于治疗任何阶段的基因融合突变患者。该公司还将明确是否需要验证性或批准后的研究，也就是被授予加速批准后需要的试验。SVB Securities写道：“虽然我们不了解交易的细节，也不知道BMS对此次会议的期望。但我们认为，鉴于该药已经有三项突破性治疗认定，交易不太可能会终止，这也表明BMS认为该药与众不同。”BMS拥有好几款治疗NSCLC药物，有些已获批，有些正在开发，包括Opdivo、Yervoy、Opdualag和CC-90011；不过，SVB Securities认为这些药物都没有靶向ROS1，所以不会造成垄断。参考文献：UPDATE：Bristol Myers strikes up Roche rivalry with $4.1B Turning Point buy识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

并购突破性疗法免疫疗法加速审批

100 项与 Pulrodemstat 相关的药物交易

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研发状态

适应症	最高研发状态	国家/地区	公司
晚期癌症	临床2期	法国更多	Celgene Corp. 更多
广泛期小细胞肺癌	临床1期	西班牙更多	Celgene Corp. 更多
急性髓性白血病	终止	比利时更多	Celgene Corp. 更多
复发性实体肿瘤	终止	西班牙更多	Celgene Corp. 更多
非霍奇金淋巴瘤	终止	意大利更多	Celgene Corp. 更多

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临床结果

适应症

分期

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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


NCT04350463 (WCLC2023) 人工标引	临床2期	晚期肺腺癌	88	CC-90011+Nivolumab (ICI-naive patients with ES SCLC)	製憲夢遞廠鹽淵遞淵淵(廠廠網鏇選選齋顧膚網) = 糧廠觸齋齋築鏇壓獵廠繭齋鏇艱壓襯觸膚製網 (顧鹽壓鹽淵願醖顧糧壓, 2.9 ~ 24.2)	不佳	2023-09-12
NCT04350463 (WCLC2023) 人工标引	临床2期	晚期肺腺癌	88	CC-90011+Nivolumab (patients with ES SCLC)	-	不佳	2023-09-12
NCT02875223 (CC-90011-ST-001, Pubmed) 人工标引	临床1期	肿瘤	69	CC-90011 (dose-escalation)	鏇顧範夢繭鹽選蓋鹹繭(膚鏇網鬱淵衊憲膚窪壓) = 夢艱觸鏇衊糧鑰獵糧廠觸願蓋蓋願範餘醖顧窪 (顧遞選蓋窪範糧醖鬱壓 )	积极	2022-06-23
NCT02875223 (CC-90011-ST-001, Pubmed) 人工标引	临床1期	肿瘤	69	CC-90011 (dose-expansion)	餘蓋窪醖積顧夢鬱齋鹽(艱襯構餘獵網醖構網鬱) = 鹽廠鹹鬱襯蓋蓋餘選願簾製築遞憲壓壓範憲繭 (衊膚繭鑰艱繭鏇夢醖鏇 )	积极	2022-06-23
NCT02875223 (CC-90011-ST-001, Pubmed \| Clin Cancer Res)	临床1期	难治性非霍奇金淋巴瘤 \| HR阳性/HER2低表达实体瘤	-	CC-90011	顧膚積壓製製製餘鏇窪(範衊鹽網醖憲齋餘襯膚) = 觸範壓觸夢醖範構築願膚遞窪鏇壓鏇鬱顧窪鬱 (艱鏇鹹廠夢襯願願製築 ) 更多	-	2021-01-15
NCT02875223 (CC-90011-ST-001, ESMO2020)	临床1期	难治性非霍奇金淋巴瘤 \| 晚期恶性实体瘤	-	CC-90011	蓋鏇簾範襯簾鏇艱獵積(蓋鬱獵齋構顧壓鬱淵鑰) = 繭衊構餘構積鏇廠積衊選鹹網鬱膚鬱齋鑰構網 (鏇鏇築網獵壓鹽簾鏇艱, 10.0 ~ 33.7)	积极	2020-09-20
NCT03850067 (ESMO2020) 人工标引	临床1期	广泛期小细胞肺癌一线	13	CC-90011+etoposide+cisplatin	鹹壓壓壓糧獵鑰憲衊鑰(憲夢壓選淵襯選淵憲齋) = 壓蓋衊膚窪醖顧獵鹹積膚觸醖淵餘衊鹹糧蓋艱 (壓製衊蓋蓋鹽艱蓋醖夢 ) 更多	积极	2020-09-17
NCT02875223 (ESMO2019) 人工标引	临床1期	难治性非霍奇金淋巴瘤 \| HR阳性/HER2低表达实体瘤	50	Pulrodemstat	鹽齋顧鹹夢繭簾壓壓選(範繭願餘膚積積襯淵衊) = 範艱齋構鑰襯築鏇襯遞衊繭顧蓋製願築鹽齋積 (鹽艱齋襯繭襯繭襯網繭 ) 更多	积极	2019-02-01