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 相关的专利（医药）

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项与 Pulrodemstat 相关的文献（医药）

2024-06-04·BIOCHEMISTRY

Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates

Article

作者: Deniz, Emre ; Uren, Aykut ; Helmbreck, Joceline ; Schneider, Owen ; Mardikar, Aashay ; Zeng, Danyun ; Reiter, Nicholas J. ; Priyankara, Indunil K. ; Senanayaka, Dulmi

Lysine specific demethylase-1 (LSD1) serves as a regulator of transcription and represents a promising epigenetic target for anticancer treatment. LSD1 inhibitors are in clinical trials for the treatment of Ewing's sarcoma (EWS), acute myeloid leukemia, and small cell lung cancer, and the development of robust inhibitors requires accurate methods for probing demethylation, potency, and selectivity. Here, the inhibition kinetics on the H3K4me2 peptide and nucleosome substrates was examined, comparing the rates of demethylation in the presence of reversible [CC-90011 (PD) and SP-2577 (SD)] and irreversible [ORY-1001 (ID) and tranylcypromine (TCP)] inhibitors. Inhibitors were also subject to viability studies in three human cell lines and Western blot assays to monitor H3K4me2 nucleosome levels in EWS (TC-32) cells, enabling a correlation of drug potency, inhibition in vitro, and cell-based studies. For example, SP-2577, a drug in clinical trials for EWS, inhibits activity on small peptide substrates (K_i = 60 ± 20 nM) using an indirect coupled assay but does not inhibit demethylation on H3K4me2 peptides or nucleosomes using direct Western blot approaches. In addition, the drug has no effect on H3K4me2 levels in TC-32 cells. These data show that SP-2577 is not an LSD1 enzyme inhibitor, although the drug may function independent of demethylation due to its cytotoxic selectivity in TC-32 cells. Taken together, this work highlights the pitfalls of using coupled assays to ascribe a drug's mode of action, emphasizes the use of physiologically relevant substrates in epigenetic drug targeting strategies, and provides insight into the development of substrate-selective inhibitors of LSD1.

2024-03-01·Journal of lipid research

Histone demethylase KDM1A promotes hepatic steatosis and inflammation by increasing chromatin accessibility in NAFLD

Article

作者: Shu, Rui ; Cai, Zhiwei ; Liu, Xiang ; Zhang, Xiao-Jing ; Yang, Zifeng ; Qu, Weiyi ; Zhang, Siyao ; Liu, Yemao ; Wang, Ye ; Li, Hongliang ; Shi, Wei ; Cheng, Xu ; Liu, Dianyu ; Bai, Lan ; She, Zhi-Gang

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific Food and Drug Administration-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as lysine-specific histone demethylase 1, has been reported to increase glucose uptake in hepatocellular carcinoma. In addition, a recent study suggests that inhibition of KDM1A reduces lipid accumulation in primary brown adipocytes. We here investigated the role of KDM1A, one of the most important histone demethylases, in NAFLD. In this study, we observed a significant upregulation of KDM1A in NAFLD mice, monkeys, and humans compared to the control group. Based on these results, we further found that the KDM1A can exacerbate lipid accumulation and inflammation in hepatocytes and mice. Mechanistically, KDM1A exerted its effects by elevating chromatin accessibility, subsequently promoting the development of NAFLD. Furthermore, the mutation of KDM1A blunted its capability to promote the development of NAFLD. In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.

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.

项与 Pulrodemstat 相关的新闻（医药）

2025-05-21

·精准药物

【JMC】郑州大学余斌/宋宜辉揭示LSD1新型结合位点与变构调节机制，助力创新药物开发

近日，郑州大学余斌/宋宜辉在国际权威药物化学期刊《Journal of Medicinal Chemistry》上发表了一篇题为“揭示LSD1的新型结合位点及其变构调节机制以助力新型治疗药物研发”的研究论文。该研究通过深入探索赖氨酸特异性去甲基化酶1（LSD1）的新型结合位点和变构调节机制，为开发新一代LSD1抑制剂提供了重要的结构基础和理论支持。一分钟速览研究背景赖氨酸特异性去甲基化酶1（LSD1）是一种关键的表观遗传调控因子，通过去甲基化功能和非酶功能参与多种细胞过程和基因表达调控。LSD1在多种疾病中发挥重要作用，包括急性髓系白血病、小细胞肺癌、尤因肉瘤、阿尔茨海默病和镰状细胞贫血等。尽管已有多种LSD1抑制剂进入临床试验，但现有的抑制剂主要针对其去甲基化功能，存在药物抗性、非靶向效应以及无法完全调节LSD1非酶功能等问题，限制了其临床疗效。因此，开发能够同时调节LSD1酶活性和非酶功能的新型抑制剂具有重要的临床意义。重点内容本研究聚焦于一种新型变构抑制剂SP2509，通过结合分子动力学模拟和生化实验验证，揭示了SP2509与LSD1的两种新结合模式。这些结合模式能够改变LSD1底物结合口袋的构象，阻断H3底物的结合，从而抑制LSD1的去甲基化活性。研究发现，SP2509的一种结合模式（min0）能够通过变构效应显著影响LSD1的Tower/CoREST结构域，使其发生弯曲，这一效应在以往的实验和计算研究中未曾报道。通过生化实验验证，研究团队进一步确认了SP2509在min0结合位点的变构调节机制，发现E379A突变显著降低了SP2509的抑制活性，而K359A突变影响较小。这表明E379与SP2509之间的卤键比K359与SP2509之间的静电相互作用更强且更稳定。研究总结本研究通过分子动力学模拟和生化实验相结合的方法，揭示了LSD1的新型结合位点和变构调节机制。SP2509作为一种新型变构抑制剂，能够通过改变LSD1的构象来抑制其去甲基化活性和非酶功能。研究结果不仅为设计能够同时调节LSD1酶活性和非酶功能的新型抑制剂提供了宝贵的结构信息，也为开发针对多种疾病的创新疗法奠定了理论基础。图片来源：ACS详细阅读01Background研究背景赖氨酸特异性去甲基化酶1（LSD1）作为一种关键的表观遗传调控因子，自2004年被发现以来，其在染色质修饰复合物的组装和转录因子网络中发挥着重要作用。LSD1通过其经典的去甲基化活性，调节组蛋白和非组蛋白的功能，进而影响基因表达和细胞过程。此外，LSD1还通过与多种蛋白的相互作用发挥非酶功能，这些相互作用使其能够调节多种细胞生物学过程。针对LSD1的抑制剂在治疗多种疾病（包括癌症和神经退行性疾病）中展现出潜在的治疗价值，但现有的临床阶段抑制剂主要靶向其去甲基化功能，存在药物抗性、潜在的非靶向效应、安全性问题以及无法完全调节LSD1的非酶功能等挑战，限制了其治疗效果。因此，开发能够同时调节LSD1去甲基化和非酶功能的新型抑制剂具有重要意义。变构抑制剂SP2509能够抑制LSD1的去甲基化和非酶功能，展现出治疗潜力，但其结合模式尚未明确。本研究旨在通过揭示SP2509的分子结合模式和机制，为设计新一代LSD1抑制剂提供结构基础。02Drug Design药物设计①通过漏斗元动力学（funnel metadynamics，FM）模拟来研究SP2509与LSD1的结合模式通过计算所有结合状态的结合自由能，作者识别出SP2509与LSD1的最优结合模式。模拟结果显示，SP2509在FM模拟中采样的空间（用橙色区域表示）表明其在结合口袋中不断探索结合和未结合区域。结合自由能随模拟时间稳定，表明模拟结果收敛。通过分析一维（1D）和二维（2D）自由能表面（FES），作者发现SP2509存在两种可能的最优结合模式，分别位于1.7 nm和2.3 nm的势能最低点，且这两种模式的势能均接近0 kcal/mol。此外，通过分析SP2509与LSD1之间的关键相互作用，特别是氯原子与LSD1中K359的质子化氮原子之间的静电相互作用，作者进一步定义了另一个集体变量（CV2）。最终，通过二维BFES分析，识别出三个能量低于1 kcal/mol的结合模式，这些模式均表现出SP2509的氯原子与LSD1中K359的稳定相互作用。这些结果为理解SP2509的结合机制提供了重要的结构信息，并为进一步的实验验证和药物设计奠定了基础。图片来源：ACS②最优结合模式基于当前最先进的力场精度，作者认为势能均值低于1 kcal/mol的构象被认为是等能的，并且构成了最优结合状态。通过对每个最优结合态的所有帧进行分析，定义了代表性结合模式，选择标准是包含该状态下最频繁出现的关键相互作用，并尽可能多地包含总体关键相互作用。具体而言，三个结合模式（min0、min1和min2）分别具有2、1和3个频率超过60%的关键相互作用。这些关键相互作用主要涉及SP2509中的氯原子，通过与LSD1中K359或K372的质子化氮原子的静电相互作用，或与E376或E379的负电氧原子的卤键相互作用。这些发现突显了SP2509中大多数原子的显著灵活性。此外，min0和min1结合模式的结合位点和关键相互作用相似，而min2结合模式则明显不同。这些详细的结合模式分析为理解SP2509如何通过不同的结合方式影响LSD1的构象和功能提供了重要的结构基础。图片来源：ACS③无偏分子动力学（MD）模拟来验证和分析SP2509与LSD1复合物的结合模式稳定性通过对LSD1及其配体的Cα原子和非氢原子的均方根偏差（RMSD）分析，结果显示在所有模拟状态下，复合物在最后300纳秒内达到了平衡状态，表现出稳定的构象波动。与CC-90011相比，SP2509和SP2577在两个结合位点（分别称为SP2509/SP2577 min0和SP2509/SP2577 min2）的稳定性较低。为了探究SP2509和SP2577的结合模式在无偏MD模拟过程中是否发生变化，作者计算了用于重建二维自由能表面（BFES）的两个距离（CV1和CV2）的时间演化。结果表明，只有在与SP2509 min0和SP2577 min0复合的LSD1中，CV2偶尔显示出显著偏差。结构分析发现，这些CV2的偏差是由于K359侧链的柔性导致的，其构象间歇性地从指向SP2509转变为指向溶剂，类似于在晶体结构中观察到的构象。这些发现表明，通过FM模拟识别的主要结合模式在无偏MD模拟过程中保持稳定。图片来源：ACS03In vitro In Vivo体内外评价①SP2509是LSD1/CoREST复合物中Tower结构域的变构调节剂作者通过主成分分析（PCA）比较了LSD1在不同结合条件下的构象状态，包括apo形式、与SP2509结合以及与两种临床试验抑制剂（SP2577和CC-90011）结合的情况。研究发现，CoREST的结合显著影响了LSD1的构象，使其在没有CoREST时表现出更广泛的PC1值分布，而CoREST结合则将其限制在一个更狭窄且一致的范围内，且这种影响与配体类型或结合位点无关。有趣的是，SP2509 min0结合（包括SP2509 min0和SP2509 min0-fixed）进一步将PC1分布限制在更小的值，表明其对LSD1具有独特的调节作用。结构分析显示，PC1代表了Tower结构域相对于Sα1螺旋片段（残基373-395）的垂直运动，而PC2描述了Tower结构域沿Sα1螺旋的运动。CoREST的结合使LSD1的Tower结构域呈现出更直立的构象，这对于CoREST与组蛋白和DNA组分在LSD1核小体底物中的相互作用至关重要。除了SP2509 min0结合外，其他配体的结合并未显著改变这一状态。SP2509 min0和SP2509 min0-fixed结合均导致Tower/CoREST区域弯曲，表明这种效应并非偶然。然而，另一个LSD1与SP2509 min0结合的模拟轨迹（称为SP2509 min0-parallel）并未表现出这种独特效应。这些结果表明，SP2509作为一种变构调节剂，能够通过影响Tower结构域的构象来调节LSD1的功能，这种调节作用可能对LSD1与核小体底物的相互作用产生重要影响。图片来源：ACS②球状结构域的复杂构象动态作者通过主成分分析（PCA）研究了LSD1的球状结构域在不同结合条件下的构象动态。与整体LSD1结构的主要构象动态主要由前两个主成分（PCs）捕获不同，球状结构域的构象动态更为复杂，前两个主成分仅能解释34.3%的累积方差。分析前四个主成分（PC1-4）的分布表明，CoREST、配体类型和结合位点等多种因素共同影响球状结构域的构象变化。此外，通过详细分析LSD1的底物结合口袋沿PC1和PC2的运动，揭示了其复杂且灵活的动态特性。这些发现强调了LSD1底物结合口袋的高度适应性和动态性，这种动态特性难以从X射线晶体学和冷冻电镜等静态结构数据中捕捉到。图片来源：ACS③详细的结合模式诱导Tower/CoREST结构域的变构弯曲作者详细分析了SP2509和SP2577在不同结合位点（min0和min2）上的结合模式，并探讨了这些结合模式如何诱导LSD1的Tower/CoREST结构域发生别构弯曲。研究发现，SP2509在min0结合位点时，其苯酚羟基指向底物结合口袋的内部，导致配体与Sα1区域的距离较远，从而形成了一个较大的结合口袋。这种独特的口袋形状使得Tower/CoREST结构域能够发生弯曲。相比之下，SP2509在min0-parallel结合模式以及SP2577在min0结合模式下，苯酚羟基指向外部，导致结合口袋变小，不利于Tower/CoREST结构域的弯曲。此外，作者通过主成分分析（PCA）进一步确认了结合口袋的形状（而非特定残基）是影响Tower/CoREST结构域弯曲的关键因素。这些结果表明，SP2509的结合模式能够通过改变结合口袋的形状，诱导LSD1的Tower/CoREST结构域发生变构弯曲，从而可能影响其与核小体底物的相互作用。图片来源：ACS④生化实验验证了SP2509与LSD1在min0结合位点的变构结合模式研究发现，E379和K359在所有min0结合配置中均参与了关键相互作用，表明它们在SP2509介导的别构调节中起着至关重要的作用。为了验证这一点，作者测试了E379A和K359A突变对LSD1与H3K4me2底物结合亲和力的影响，以及对SP2509抑制活性的影响。结果显示，E379A突变显著降低了LSD1对H3K4me2的结合亲和力（KM值显著增加），同时也降低了SP2509对LSD1/CoREST复合物的抑制活性（IC50和Ki值显著增加）。相比之下，K359A突变对SP2509的抑制活性影响较小。这些结果表明，E379与SP2509之间的卤键比K359与SP2509之间的静电相互作用更强且更稳定。这些发现进一步证实了SP2509在min0结合位点的别构调节机制，并为设计针对LSD1的新型抑制剂提供了重要的结构基础。图片来源：ACS总结目前处于临床阶段的LSD1抑制剂主要靶向其去甲基化功能，而靶向LSD1的非酶功能的抑制剂仍处于初级阶段。SP2509作为一种代表性的变构抑制剂，能够同时抑制LSD1的酶活性和非酶功能，因此对于探究抑制机制具有重要价值。通过广泛的漏斗元动力学（FM）和无偏分子动力学（MD）模拟，本研究揭示了SP2509在LSD1上的两个新的结合位点，这些结合位点能够诱导底物结合口袋入口处的构象变化，从而阻碍H3底物的结合并抑制LSD1的去甲基化活性。特别值得注意的是，SP2509在“min0”结合位点的结合能够对Tower/CoREST结构域产生别构效应，导致该结构域显著弯曲，这可能干扰LSD1/CoREST与核小体底物的相互作用。此外，生化实验验证了SP2509在min0结合位点的别构调节机制，突变分析表明E379A突变显著降低了SP2509的抑制活性，而K359A突变影响较小。这些结果表明E379与SP2509之间的卤键比K359与SP2509之间的相互作用更强且更稳定。综上所述，这些发现为设计能够同时靶向LSD1的酶活性和非酶功能的新一代抑制剂提供了结构基础，并可能推动针对多种疾病的新型疗法的开发。参考来源：https://doi.org/10.1021/acs.jmedchem.5c00966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↓

蛋白降解靶向嵌合体

2023-09-19

·SYNAPSE

LSD1 inhibitors - A potent inhibitory target for tumor immunotherapy

The catalytic function of LSD1(KDM1A)depends on the flavin adenine dinucleotide (FAD) and it is a member of the monoamine oxidase family. LSD1 consists primarily of three parts: the N-terminal SWIRM domain; the C-terminal amine oxidase (AOL) domain, which is divided into the FAD-binding domain and the substrate-binding domain, forming the catalytic activity center; and the centrally located Tower domain. The Tower domain has two anti-balanced α-helices, playing a crucial role in LSD1's activity. LSD1 can regulate the expression of tumor-associated genes, promoting the proliferation, invasion, and metastasis of tumor cells. Current research has proven that LSD1 plays a critically regulatory role in hematological malignancies, such as acute granulocytic leukemia. LSD1 has also been found to show abnormal expression in a variety of solid tumors, closely related to tumor tissue grading, malignancy degree, and prognosis. LSD1, also known as lysine-specific demethylase 1A, is an enzyme that plays a crucial role in the regulation of gene expression in the human body. It functions by removing specific methyl groups from histone proteins, which are involved in the packaging of DNA. By demethylating histones, LSD1 helps to activate or repress gene transcription, thereby influencing various cellular processes such as cell differentiation, development, and response to environmental stimuli. Dysregulation of LSD1 has been implicated in several diseases, including cancer and neurodegenerative disorders. Understanding the role of LSD1 can provide valuable insights for the development of targeted therapies in the pharmaceutical industry. LSD1 Competitive LandscapeAccording to the data provided by Patsnap Synapse-Global Drug Intelligence Database: the following figure shows that as of 18 Sep 2023, there are a total of 36 LSD1 drugs worldwide, from 36 organizations, covering 66 indications, and conducting 75 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target. The analysis of the target LSD1 reveals a competitive landscape with multiple companies actively developing drugs at different stages of development. Oryzon Genomics SA stands out with the highest stage of development and multiple drugs in different stages. The indications for the target LSD1 cover a wide range of diseases, with Phase 2 being the highest phase of development. Small molecule drugs are progressing rapidly, indicating a focus on developing innovative therapies. China, the United States, and the European Union are leading in terms of development, with other countries/locations also actively contributing to the research and development of LSD1-targeted therapies. Overall, the target LSD1 shows promising potential for future development in the pharmaceutical industry. Irreversible LSD1 Inhibitor - LadademstatLadademstat is a small molecule drug targeting KDM1A developed by Oryzon company. The AML trial (ALICE) data announced at the 2022 EHA showed that the overall response rate (ORR) reached 81% in 36 patients when Ladademstat was combined with azacitidine, and 64% of the CR/CRi responses were lasting (more than 6 months). By the end of the cycle, 91% of the patients had a response. In terms of safety, thrombocytopenia was observed in about half of the patients (53%), with one patient experiencing a serious adverse event. No other significant non-hematological toxicity or organ-related toxicity were observed. In terms of therapeutic areas, Iadademstat is primarily being studied for its efficacy in treating neuroendocrine carcinoma, small cell lung cancer, acute myeloid leukemia (AML), and FLT3 positive AML. These indications represent a range of malignancies affecting different organs and systems in the body. Currently, Iadademstat has reached the highest phase of clinical development, which is Phase 2. Phase 2 trials aim to further evaluate the drug's effectiveness and side effects in a larger patient population. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. In terms of regulatory status, Iadademstat has been designated as an orphan drug. Orphan drug status is granted to drugs that are intended to treat rare diseases or conditions, providing incentives to pharmaceutical companies to develop therapies for these unmet medical needs. Based on the available information, Iadademstat shows promise as a potential treatment option for various types of cancer, including neuroendocrine carcinoma, small cell lung cancer, and AML. However, further clinical trials and research are needed to fully assess its safety and efficacy. The orphan drug designation suggests that Iadademstat may address unmet medical needs in these specific indications. Reversible LSD1 Inhibitor: PulrodemstatPulrodemstat (CC-90011) is the first reversible LSD1 inhibitor to enter clinical research, with an IC50 for LSD1 of 0.25 nmol·L−1. A phase I/II clinical trial was conducted with CC-90011 to evaluate the safety, tolerability, and efficacy of CC-90011 in conjunction with traditional AML treatments (venetoclax and azacytidine). The study showed that the use of CC-90011 with traditional AML treatments can inhibit LSD1 activity and increase the sensitivity of AML patients to traditional treatments. CC-90011-ST-001 is a phase I, multicentre, dose-escalation study, exploring nine dosage levels of CC-90011 (1.25-120mg). The primary objectives are to determine the safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D), with secondary objectives of assessing preliminary efficacy and pharmacodynamics. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. In the field of oncology, Pulrodemstat has shown promise in treating acute myeloid leukemia, myeloid leukemia, non-small cell lung cancer, squamous cell carcinoma, small cell lung cancer, adenocarcinoma, hormone refractory prostate cancer, non-Hodgkin lymphoma, and solid tumors. These indications cover a wide range of cancer types, suggesting that Pulrodemstat may have broad applicability in the treatment of various malignancies. As a small molecule drug, Pulrodemstat is likely to have advantages in terms of its pharmacokinetic properties, such as oral bioavailability and tissue penetration. These characteristics can contribute to its effectiveness and ease of administration. In summary, Pulrodemstat is a small molecule drug that targets KDM1A and is being developed by Quanticel Pharmaceuticals, Inc. It has shown potential in treating various therapeutic areas, particularly in the field of oncology. With its current status in Phase 2 of clinical trials, Pulrodemstat represents a promising candidate for the treatment of a range of diseases, including acute myeloid leukemia, non-small cell lung cancer, and hormone refractory prostate cancer, among others.

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

100 项与 Pulrodemstat 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
晚期癌症	临床2期	美国	Celgene Corp.	2020-07-14
晚期癌症	临床2期	法国	Celgene Corp.	2020-07-14
晚期癌症	临床2期	意大利	Celgene Corp.	2020-07-14
晚期癌症	临床2期	波兰	Celgene Corp.	2020-07-14
晚期癌症	临床2期	西班牙	Celgene Corp.	2020-07-14
晚期癌症	临床2期	英国	Celgene Corp.	2020-07-14
难治性急性髓细胞白血病	临床1期	美国	Celgene Corp.	2021-10-14
难治性急性髓细胞白血病	临床1期	比利时	Celgene Corp.	2021-10-14
难治性急性髓细胞白血病	临床1期	法国	Celgene Corp.	2021-10-14
难治性急性髓细胞白血病	临床1期	西班牙	Celgene Corp.	2021-10-14

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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 (CTgov)	临床2期	晚期癌症	92	CC-90011+Nivolumab (Cohort A 40 mg)	窪顧壓鏇淵憲夢觸簾範 = 鹽蓋鹽範餘齋網膚鬱夢願積構簾遞壓餘蓋艱鏇 (窪獵鏇網選膚鹹糧遞鑰, 餘艱鹹遞衊觸膚艱廠糧 ~ 鹽衊鏇鏇繭醖醖觸糧鬱) 更多	-	2025-01-22
				CC-90011+Nivolumab (Cohort A 60mg)	窪顧壓鏇淵憲夢觸簾範 = 鏇蓋廠蓋艱鑰築窪鹹願願積構簾遞壓餘蓋艱鏇 (窪獵鏇網選膚鹹糧遞鑰, 獵鬱觸鑰齋繭窪鹹願簾 ~ 鏇獵蓋願蓋願壓壓齋顧) 更多
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)	鏇淵鑰餘鑰鬱淵觸遞鏇(選膚糧獵廠壓獵網觸鹽) = 膚糧鏇鏇夢積願糧網窪遞夢製艱顧鏇廠糧積襯 (繭繭膚醖襯醖衊膚築膚, 2.9 ~ 24.2)	不佳	2023-09-12
				CC-90011+Nivolumab (patients with ES SCLC)	-
NCT02875223 (CC-90011-ST-001, Pubmed) 人工标引	临床1期	肿瘤	69	CC-90011 (dose-escalation)	襯願觸窪簾選範積觸鏇(壓餘範齋築觸衊網鹹壓) = 範繭鹹廠壓鏇積鑰壓鹽繭願簾繭糧醖繭願鏇鑰 (獵窪願蓋觸觸齋觸網醖 )	积极	2022-06-23
				CC-90011 (dose-expansion)	窪鬱鹹觸繭糧積築繭鬱(觸獵構糧築壓憲選製願) = 艱選鹹餘製積選範遞鹹淵鏇積醖鹹鹹衊繭鏇壓 (構艱窪簾襯糧鑰繭獵遞 )
NCT03850067 (CC-90011-SCLC-001, ESMO_ELCC2021)	临床1期	广泛期小细胞肺癌一线	-	CC-90011 + EP	鏇構膚鹽窪繭願鑰鹹憲(鏇積顧衊壓膚窪齋衊齋) = 網艱範壓獵糧鏇鏇壓鏇繭壓蓋糧襯製膚窪製鏇 (獵選艱齋襯遞蓋膚範醖 ) 更多	-	2021-03-24
				CC-90011 + EC	繭獵膚簾鹹願鏇淵膚鏇(構糧鏇糧構壓觸衊餘餘) = 蓋鏇襯廠選糧觸獵膚窪鬱鑰鹽齋餘鹹繭糧繭積 (蓋顧衊獵窪範憲廠糧壓 )
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	艱淵鏇網範膚糧廠憲鹽(網夢淵遞壓鏇選顧襯醖) = 繭獵觸鹽選襯鏇積膚築餘顧蓋鏇選鹽衊選選蓋 (遞鏇製蓋鬱齋構蓋鹽膚, 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	構構構醖蓋遞鏇鏇鏇淵(遞艱遞繭蓋鏇積醖鑰簾) = 鏇鏇積廠壓鹽築範鹽繭鑰鏇蓋觸鹽簾獵鏇繭鬱 (衊艱繭築獵製鏇廠憲夢 ) 更多	积极	2020-09-17
NCT02875223 (ESMO 12019 \| ESMO 22019) 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	壓獵遞獵壓遞築鏇簾廠(構選壓鹹繭鑰鹽淵築窪) = 範範鑰艱淵艱蓋顧襯醖願窪鹹鹽廠築壓鏇艱製 (鹹構鬱簾鏇糧醖襯窪鬱 ) 更多	积极	2019-02-01