Samuraciclib hydrochloride

As VERZENIO gains traction in early-stage treatments and broadens its approved uses, its revenue is expected to keep growing. While the global CDK4/6 inhibitor market remains highly competitive, VERZENIO's distinct clinical advantages and ongoing studies could contribute to further market expansion. LAS VEGAS, March 13, 2025 /PRNewswire/ -- DelveInsight's " VERZENIO Market Size, Forecast, and Market Insight Report" highlights the details around VERZENIO, which is a targeted treatment known as a CDK4/6 inhibitor. The drug is a non-chemotherapy oral tablet. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of VERZENIO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Eli Lilly and Company's VERZENIO (abemaciclib) Overview VERZENIO (abemaciclib) is a prescription medication used to treat adults with HR-positive, HER2-negative breast cancer that has metastasized (spread to other parts of the body). It is administered orally and is prescribed in combination with an aromatase inhibitor as an initial endocrine-based therapy. Additionally, the drug is being developed for the treatment of prostate cancer. VERZENIO is approved for the following indications: In combination with endocrine therapy for the adjuvant treatment of adults with HR+/HER2-, node-positive, early-stage breast cancer at high risk of recurrence. In combination with an aromatase inhibitor as the initial endocrine-based therapy for adults with HR+/HER2- advanced or metastatic breast cancer. In combination with fulvestrant for adults with HR+/HER2- advanced or metastatic breast cancer that has progressed after prior endocrine therapy. As monotherapy for adults with HR+/HER2- advanced or metastatic breast cancer that has progressed following endocrine therapy and prior chemotherapy in the metastatic setting. Learn more about VERZENIO projected market size for breast cancer @ VERZENIO Market Potential HR+/HER2- breast cancer is the most common subtype of breast cancer, defined by the presence of estrogen and progesterone hormone receptors but lacking HER2 overexpression. This form of breast cancer generally has a favorable prognosis and is primarily managed with hormone therapy to suppress hormone-driven tumor growth. According to DelveInsight's estimates, around 211,000 new cases of HR+/HER2− breast cancer were reported in the US in 2024. Over the past decade, endocrine therapy has remained the cornerstone of treatment, including for cases with visceral involvement. The current preferred approach involves combining endocrine therapy—using aromatase inhibitors or fulvestrant—with CDK4/6 inhibitors. The approval of CDK4/6 inhibitors has significantly transformed the treatment landscape for HR+/HER2− breast cancer. Currently, five selective CDK4/6 inhibitors— ENHERTU, DATROWAY, IBRANCE, KISQALI, and VERZENIO—are used in combination with endocrine therapy. In November 2023, the FDA approved TRUQAP (capivasertib) in combination with FASLODEX for patients with advanced HR+/HER2− breast cancer harboring specific biomarker alterations (PIK3CA, AKT1, or PTEN). The NCCN Guidelines have designated KISQALI as the only Category 1 Preferred CDK4/6 inhibitor for first-line treatment in combination with an aromatase inhibitor, strengthening its position in the U.S. market. This led to KISQALI recovering its lost market share, with its U.S. revenue contribution rebounding to 50%, following declines to 46% in 2020, 36% in 2021, and 38% in 2022. In January 2025, the FDA approved DATROWAY for patients with unresectable or metastatic HR+/HER2- breast cancer (IHC 0, IHC 1+, or IHC 2+/ISH-) who had previously received endocrine-based therapy and chemotherapy. Additionally, ENHERTU was approved for patients with unresectable or metastatic HR+, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer that had progressed after at least one prior endocrine therapy in the metastatic setting. Also, in January 2025, Roche reported positive topline results from its Phase III INAVO120 trial, assessing ITOVEBI in combination with IBRANCE and fulvestrant for patients with PIK3CA-mutated HR+/HER2−, endocrine-resistant, locally advanced, or metastatic breast cancer. Among the seven major markets, the US accounted for the largest market share in HR+/HER2− breast cancer, generating USD 7.5 billion in revenue in 2023. The market is expected to experience substantial growth from 2025 to 2034, driven by the introduction of novel therapeutic options. Discover more about the breast cancer market in detail @ Metastatic HR+/HER2- Breast Cancer Market Report Emerging Competitors of VERZENIO Some of the competing emerging key players in HR+/HER2- breast cancer market are, Merck (KEYTRUDA), Arvinas (ARV-471 (vepdegestrant)), Olema Pharmaceuticals (OP1250 (palazestrant)), Celcuity (Gedatolisib), Roche (Giredestrant (RG6171, GDC-9545); Inavolisib), AstraZeneca and Daiichi Sankyo (Datopotamab Deruxtecan (Dato-DXd)), AstraZeneca (Camizestrant (AZD9833); Capivasertib), Eli Lilly (LY3484356/Imlunestrant), Sermonix Pharmaceuticals (Lasofoxifene), Veru Pharma (Enobosarm), DualityBio/BioNtech (DB-1303), Evgen Pharma (SFX-01), Carrick Therapeutics (Samuraciclib (CT-7001)), EQRx/G1 Therapeutics (Lerociclib), Immutep (Eftilagimod Alpha (LAG-3lg/IMP321)), and others. To know more about the number of competing drugs in development, visit @ VERZENIO Market Positioning Compared to Other Drugs Key Milestones of VERZENIO In 2024, Phase III trials did not meet primary endpoints or were terminated for futility. Negative Phase III CYCLONE-2 results, in which VERZENIO added to abiraterone did not meet the primary endpoint of improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC). In December 2023, Eli Lilly and Company presented results from the MONARCH 3 clinical trial at the 2023 San Antonio Breast Cancer Symposium (SABCS). Results from MONARCH 3 show a numerical improvement in overall survival (OS) of 13.1 months for women with HR+, HER2- metastatic breast cancer treated with VERZENIO plus an aromatase inhibitor in the intent-to-treat population and 14.9 months for women with visceral disease. In March 2023, the US FDA approved an expanded indication for VERZENIO in combination with endocrine therapy for the adjuvant treatment of adult patients with HR+/HER2−, node-positive, early breast cancer (EBC) at a high risk of recurrence. This expanded adjuvant indication removes the Ki-67 score requirement for patient selection. In February 2022, the CHMP adopted a positive opinion recommending a change to the terms of the marketing authorization for the medicinal product VERZENIO. VERZENIO, in combination with endocrine therapy, is indicated for the adjuvant treatment of adult patients with HR+/HER2− negative, node-positive early breast cancer at high risk of recurrence. In October 2021, the US FDA approved VERZENIO, in combination with endocrine therapy (tamoxifen or an aromatase inhibitor), for the adjuvant treatment of adult patients with HR+/HER2−, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of ≥20% as determined by an FDA-approved test. Ki-67 is a marker of cellular proliferation. In September 2018, VERZENIO was approved in Europe for treating advanced HR+ breast cancer in women if the cancer has already spread to other parts of the body or is locally advanced.  In September 2018, VERZENIO was approved for the treatment of patients with HR+/HER2− unresectable or recurrent breast cancer in combination with fulvestrant or an aromatase inhibitor (AI) in Japan. In February 2018, the US FDA approved VERZENIO in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with HR+/HER2− advanced or metastatic breast cancer In September 2017, the US FDA approved VERZENIO in combination with an endocrine therapy to treat adult patients who have HR+/HER2− advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient's hormones (endocrine therapy). In October 2015, the US FDA granted Breakthrough Therapy Designation to abemaciclib for patients with refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer Discover how VERZENIO is shaping the breast cancer treatment landscape @ VERZENIO Breast Cancer VERZENIO Market Dynamics The oral administration of VERZENIO enhances patient convenience, while its expanded approval for the adjuvant treatment of adult patients with HR+/HER2- early breast cancer highlights its role as a differentiated CDK4/6 inhibitor in reducing the risk of recurrence. The rising prevalence of HR+/HER2- breast cancer is driving market demand for effective treatments like VERZENIO. Additionally, its demonstrated efficacy in combination with endocrine therapy and its ability to penetrate the central nervous system further strengthen its market position. Favorable reimbursement policies and increasing awareness among healthcare providers also contribute to its adoption. However, its adoption may be hindered by regulatory hurdles and potential side effects, including severe or life-threatening lung inflammation and serious liver problems. High treatment costs and access disparities in certain regions could also limit market penetration. Competition from other CDK4/6 inhibitors such as IBRANCE and KISQALI poses a challenge, along with concerns over long-term safety data. Additionally, the Phase III CYCLONE-2 trial failed to meet primary endpoints in mCRPC, which may impact its broader clinical prospects and investor confidence. Dive deeper to get more insight into VERZENIO's strengths & weaknesses relative to competitors @ VERZENIO Market Drug Report Table of Contents Related Reports CDK4/6 Inhibitor Market CDK4/6 Inhibitor Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key CDK4/6 inhibitor companies including Pfizer, Prelude Therapeutics, G1 Therapeutics, Pepper Bio, among others. Metastatic HR+/HER2− Breast Cancer Market Metastatic HR+/HER2− Breast Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key metastatic HR+/HER2− breast cancer companies including Pfizer, Novartis, Stemline Therapeutics, Olema Pharmaceuticals, Arvinas, Immutep, AstraZeneca, Roche, Genentech, Evexta Bio, EQRx, Sermonix Pharmaceuticals, Celcuity, Veru Pharma, Evgen Pharma, Eli Lilly, Biotheryx, among others. HR+/HER2− Breast Cancer Pipeline HR+/HER2− Breast Cancer Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key HR+/HER2− breast cancer companies, including Regor Therapeuics, Seagen Inc., CytomX Therapeutics, Taizhou EOC Pharma, Chia Tai Tianqing Pharmaceutical Group, AstraZeneca, Daiichi Sankyo, Inc., Tyme, Inc., Seagen Inc., Context Therapeutics, Eisai Inc., Shanghai Hengrui Pharmaceutical Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Kind Pharmaceuticals, Merus N.V., Atossa Therapeutics, Roche, among others. Breast Cancer Market Breast Cancer Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key breast cancer companies, including Veru, Sanofi, Roche, AstraZeneca, Eli Lilly, EQRx, Gilead, Sermonix Pharmaceuticals, Evgen Pharma, Tyme, Genentech, Daiichi Sankyo, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . 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细胞周期蛋白依赖性激酶7 (CDK7) 是一种丝氨酸-苏氨酸激酶，与Cyclin H和CDK激活激酶 (MAT1) 的MNAT1组分形成三聚体CDK激活激酶 (CAK) 复合物，磷酸化下游细胞周期蛋白依赖性激酶CDK1、2、4和6。CDK1/2/4/6激活直接促进细胞周期进程。此外，CAK复合物作为转录因子IIH (TFIIH) 复合物的一部分发挥作用，并在Ser5和Ser7位点磷酸化RNA Pol II的C末端结构域 (CTD) ，这是转录起始和延伸的重要步骤。CDK7还可以直接磷酸化或调节几种关键致癌因子（如c-Myc）的表达。因此，这些功能使CDK7成为肿瘤适应症中具有吸引力的靶标。目前，几种CDK7抑制剂已进入临床试验阶段。正在进行的I/II期临床试验包括ICEC0942 (CT7001) 、SY-1365/SY-5609系列和LY3405105。其中SY-1365因静脉给药时临床活性和耐受性不佳而被停用；而SY-5609表现出较强烈的胃肠道反应和血液毒性。 为了改善上述问题，英矽智能公司以化合物SY-5609为先导化合物，经过广泛的构效关系研究和ADME优化，成功获得了强效大环非共价CDK7抑制剂化合物13，在异种移植模型中表现出优越的体外活性、良好的ADME特性和出色的体内抗肿瘤活性。更重要的是，化合物13表现出较好的Caco-2通透性，降低了大鼠的肠道分布和血液/血浆比率；从而减轻胃肠道影响和血液毒性副作用。 研究内容 1. 化合物设计及构效关系研究 作者以选择性高，药效显著但具有胃肠道反应和血液毒性等副作用的SY-5609为先导化合物，基于公开获得的来自PDB (PDB ID: 7B5O) 的CDK7晶体结构重建了同源模型。通过CDK7与SY-5609的结合模式（图1A）发现，SY-5609的氨基嘧啶和吲哚之间的二面角稳定分布在30°和40°之间。然而，SY-5609本身在其最低能量构象中具有90°的二面角。因此，作者构建了大环分子以实现与结合构象一致的低能量构象。通过大环化策略用酰胺将SY-5609的氰基位置和哌啶基连接，通过改变linker类型，形成了一系列大环化合物（图1B-D），其中化合物2和3的最低能量构象的二面角分别为38.6°和41.7°，与它们的结合模式构象的二面角分别为22.9°和41.0°相当（图1E-F）。化合物2和3均显示出有效的CDK7酶抑制活性（IC50为11 nM和4.6 nM，表1）和HCC70细胞抗增殖活性（IC50为1821 nM和207 nM），但均比SY-5609活性差。 图1 (A) SY-5609与CDK7复合物的结合方式；(B) 构建大环的连接位点; (C) linker结构；(D) 大环骨架具有最短的连接子；(E) 化合物2的最低能构象与结合构象的比较；(F) 化合物3的最低能构象与结合构象的比较[1] 为进一步提高抑制活性，在化合物3上引入二甲基氧化膦作为非典型氢键受体设计并合成化合物4（表1）。与化合物3相比，化合物4表现出高结合亲和力 (CDK7 Kd= 0.16 nM) 和更优的细胞活性 (HCC70 IC50= 33 nM) 。随后，进一步探索大环linker长度和类型。相较于化合物4，具有醚链的化合物7表现出更高的结合亲和力 (SPR Kd= 0.06 nM) 和相当的抗增殖活性 (HCC70 IC50= 29 nM) 。 表1  CDK7抑制剂的体外酶活性、结合亲和力和细胞活性[1] 进一步评估化合物4和7的体外ADME和体内小鼠PK特性（表2）。化合物4在小鼠体内的清除率中等 (49.3 mL/min/kg) ，而化合物7在小鼠体内的清除率要高得多 (95.9 mL/min/kg) ，表明它们有可能发生肝外代谢。在小鼠口服PK分析中，化合物4和7的口服生物利用度都很低（分别为0.7%和23%），可能是由于亲脂性不理想（cLogD = -0.29和0.08）、氢键供体过多以及碱性胺的pKa过高导致口服渗透性低，影响口服后的肠道吸收。 表2  化合物4和7的体外ADME和体内小鼠PK特性[1] 为了进一步优化体外ADME和体内PK特性，设计了一系列具有较高亲脂性、更少氢键供体 (HBD) 和碱性胺pKa更低的化合物（表3）。其中二氟化合物13显示出更好的Caco-2的渗透性 (3.69 × 10-6 cm/s，ER = 5.1) ，在HCC70细胞中表现出有效的细胞抑制作用（IC50= 24.6 nM）和OVCAR3 (IC50= 57.0 nM) 。 表3  CDK7抑制剂的体外结合亲和力、细胞活性和Caco-2通透性[1] 2. 体内外PK研究 与化合物1相比，化合物13表现出较低的分布容积 (VSS= 0.24 – 2.6 L/kg) 以及较短的T1/2 (0.6 ~ 3.4 h) ，且化合物13的碱度降低会降低肠道分布、保留时间和血浆比率。这些特征可以防止潜在的胃肠道副作用和血液毒性（图2A）。在多个不同物种（大鼠、狗和小鼠）中，化合物13也显示出良好的血浆暴露和口服生物利用度（图2C）。此外，化合物13的肠道和血浆浓度下降速度比化合物1快很多，这可能是由于其T1/2 较短，可能有利于减轻药物不良反应（图2D）。在体外ADME和安全性方面（图2B），化合物13表现出良好的理化特性，具有足够的PBS溶解度 (917 μg/mL) 。体外微粒体代谢稳定性表明，化合物13在人、小鼠和大鼠的清除率相对较高，人的血浆稳定性良好 (T1/2 > 289 min) 。体外安全性分析表明，在所有测试的CYP同工酶中，都没有强效的CYP抑制作用，且hERG风险较低 (IC50= 9.94 μM) 。与此相反，化合物1对CYP2D6有强效抑制作用 (IC50= 0.075 μM) ，表明可能存在药物间相互作用 (DDI) 风险。 图2  化合物13的体内外ADME及安全性[1] 此外，激酶谱显示，化合物13表现出16-3034倍的选择性抑制作用 (Kd= 0.18 nM) ，具有良好的选择性。在OVCAR3卵巢癌异种移植模型小鼠中，2、5、10和20 mg/kg剂量的化合物13能明显抑制肿瘤生长，相对于用vehicle治疗的小鼠，TGI（肿瘤生长抑制率）约为110%；在三阴性乳腺癌 (TNBC) HCC70异种移植模型中，化合物13具有剂量依赖性抗肿瘤活性，其终点TGI分别为36% (1 mg/kg) 、120% (3 mg/kg) 和175% (10 mg/kg) 。 总结 这项研究利用大环化策略，开发了一系列新型大环化合物作为非共价CDK7抑制剂，发现化合物13具有良好的体外活性、选择性、ADME特性和Caco-2渗透性，同时表现出较短的T1/2、较高的口服暴露量和良好的生物利用度，并且由于化合物碱性降低，分布容积变小，导致大鼠肠道分布减少，血液/血浆比率降低。这些特性可能会减轻现有CDK7抑制剂的胃肠道和血液毒性副作用。此外，化合物13作为单药在OVACR3和HCC70异种移植模型中表现出了强大的抗肿瘤活性，治疗耐受性良好。 参考文献  [1] Lu H, Zhang Y, Liu J, et al. Discovery of a Novel Macrocyclic Noncovalent CDK7 Inhibitor for Cancer Therapy. Journal of Medicinal Chemistry. 2024, 67(22):20580-20594 供稿：冷利敏 校稿：陈娜/耿小菊 编辑：汤荣凡 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↓