Palazestrant(Palazestrant) - 药物靶点：ER_在研适应症：ER阳性乳腺癌，HER2 阴性乳腺癌，局部晚期乳腺癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

OP-1250

靶点

ER

作用方式

降解剂

作用机制

ERs降解剂(雌激素受体家族降解剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病泌尿生殖系统疾病

在研适应症

ER阳性乳腺癌HER2 阴性乳腺癌局部晚期乳腺癌+ [4]

非在研适应症

HR阳性乳腺腺癌HR阳性/HER2阴性乳腺癌

原研机构

Olema Pharmaceuticals, Inc.

在研机构

Olema Pharmaceuticals, Inc.

非在研机构-

权益机构

Olema Pharmaceuticals, Inc.

Pfizer Inc.

Novartis AG

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评快速通道 (美国)

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结构/序列

分子式C28H36FN3O

InChIKeyLBSFUBLFDCAEKV-XHCCPWGMSA-N

CAS号2092925-89-6

关联

6

项与 Palazestrant 相关的临床试验

NCT07085767

/ Recruiting临床3期

A Phase 3 Randomized, Double-Blind, Active-Controlled Study of Palazestrant With Ribociclib Versus Letrozole With Ribociclib for the First-Line Treatment of ER+, HER2- Advanced Breast Cancer (OPERA-02)

This phase 3 clinical trial compares the efficacy and safety of palazestrant with ribociclib to letrozole and ribociclib in women and men who have not received prior systemic anti-cancer treatment for advanced breast cancer.

开始日期2025-11-03

申办/合作机构

Olema Pharmaceuticals, Inc.

[+1]

NCT06784193

/ Recruiting临床1期

A Phase 1 First-in-Human, Open-Label, Multicenter Study of OP-3136 in Adult Participants With Advanced or Metastatic Solid Tumors

This is a first-in-human, open-label, multicenter phase 1 study to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OP-3136, a lysine acetyltransferases 6A and 6B (KAT6A/B) inhibitor, as monotherapy and in combination with other anticancer agents in participants with advanced solid tumors.
This study consists of 2 parts: a dose escalation part (Part 1) and dose expansion part (Part 2).

开始日期2024-12-16

申办/合作机构

Olema Pharmaceuticals, Inc.

NCT06016738

/ Active, not recruiting临床3期

A Phase 3 Randomized, Open-Label Study of OP-1250 Monotherapy vs Standard of Care for the Treatment of ER+, HER2- Advanced or Metastatic Breast Cancer Following Endocrine and CDK 4/6 Inhibitor Therapy (OPERA-01)

This phase 3 clinical trial compares the safety and efficacy of palazestrant (OP-1250) to the standard-of-care options of fulvestrant or an aromatase inhibitor in women and men with breast cancer whose disease has advanced on one endocrine therapy in combination with a CDK4/6 inhibitor.

开始日期2023-11-16

申办/合作机构

Olema Pharmaceuticals, Inc.

100 项与 Palazestrant 相关的临床结果

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100 项与 Palazestrant 相关的转化医学

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100 项与 Palazestrant 相关的专利（医药）

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5

项与 Palazestrant 相关的文献（医药）

2026-01-14·Future Oncology

OPERA-01: a phase III study of palazestrant for ER+, HER2– advanced breast cancer after CDK4/6 inhibitor therapy

Article

作者: Chan, Arlene ; Schmid, Peter ; Sohn, Joohyuk ; McArthur, Heather ; Bellet Ezquerra, Meritxell ; Pistilli, Barbara ; de Kermadec, Elisabeth ; Del Mastro, Lucia ; Meisel, Jane ; Zheng, Lianqing

Endocrine therapy (ET) resistance is a major concern when treating estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. A combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and ET is the current first-line standard of care (SOC) for patients with ER+, HER2- advanced breast cancer. Despite the benefits of ET plus a CDK4/6i, disease progression due to endocrine resistance remains a significant challenge. More effective ETs that can overcome resistance are needed to improve clinical outcomes and maintain quality of life by delaying chemotherapy. Palazestrant is a novel oral, complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that blocks both transcriptional activation function domains, AF1 and AF2, resulting in complete inhibition of ER-driven transcription, regardless of estrogen receptor 1 (ESR1) mutation status. As monotherapy, palazestrant showed tolerable safety, favorable pharmacokinetics, and antitumor efficacy in heavily pretreated patients during phase I/II studies. OPERA-01 (NCT06016738) is a phase III study designed to evaluate the safety and efficacy of palazestrant monotherapy compared to SOC ET in patients with ER+, HER2- locally advanced or metastatic breast cancer, regardless of ESR1 mutation status, whose disease advanced following treatment with at least one ET in combination with a CDK4/6i.Clinical Trial Registration: Clinicaltrials.gov NCT06016738. Registered 17 August 2023.

2025-06-10·ACS Omega

Discovery of Palazestrant (OP-1250), a Potent and Orally Bioavailable Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD)

Article

作者: Rich, Brian ; Yu, Guijun ; Kushner, Peter J. ; Peña, Guadalupe ; Phukan, Samiron ; Hodges-Gallagher, Leslie ; Sapugay, Judevin ; Chawla, Reena ; Andersen, Samuel E. ; Millikin, Robert ; Sun, Richard ; Parisian, Alison ; Zhou, Fei ; Duncan, Alexis ; Wang, Chenbo ; Zak, David R. ; Hearn, Brian R. ; Barratt, Susanna ; Ng, Raymond A. ; Satish Kher, Samir ; Fanning, Sean W. ; Watanabe, Teruki ; Myles, David C. ; Palanisamy, Gopinath S. ; Yeghikyan, David ; Thangathirupathy, Srinivasan ; Robello, Brandon ; Greene, Geoffrey ; Harmon, Cyrus L. ; Heerding, Dirk A.

Metastatic breast cancer (mBC) is a leading cause of cancer death in women. Most breast cancer patients are administered estrogen-receptor-targeted endocrine therapies to treat or prevent progressive metastatic disease. Development of endocrine resistance through acquisition of mutations in the estrogen receptor gene, ESR1, that constitutively activate the estrogen receptor leads to relapse. Complete antagonism of both WT and mutant ESR1 (mutESR1) with an oral therapeutic that persistently antagonizes ER-driven oncogenic transcriptional activities is a requirement for efficacy. Here, we describe our discovery of the investigational drug OP-1250 (palazestrant). OP-1250 is a potent complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that is active in both WT and mutESR1 breast cancer tumors. OP-1250's effective induction of tumor regression either as a single agent or in combination with a CDK4/6 inhibitor has led to the rapid advancement of this compound into a Phase 3 clinical trial (OPERA-01).

2024-11-01·LANCET ONCOLOGY

The state of the science of oral selective oestrogen receptor degraders

Article

作者: Mayer, Erica L ; Fanucci, Kristina

151

项与 Palazestrant 相关的新闻（医药）

2026-09-02

·BioSpace

Olema Oncology Reports Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) - September 2, 2026

SAN FRANCISCO, Sept. 02, 2026 (GLOBE NEWSWIRE) -- Olema Pharmaceuticals, Inc. (“Olema” or “Olema Oncology”, Nasdaq: OLMA), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of targeted therapies for breast cancer and beyond, today announced that, in connection with the appointment of Jason V. O’Byrne as Chief Financial Officer effective August 11, 2026, the Company granted Mr. O’Byrne an employment inducement award consisting of stock options to purchase 650,000 shares of the Company’s common stock, with an effective grant date of September 1, 2026 and an exercise price of $10.56 per share, equal to the last reported sale price of the Company's common stock as reported by Nasdaq on September 1, 2026. The award was approved by the Compensation Committee of Olema’s Board of Directors and granted under the Company's 2022 Inducement Plan. The stock options vest over four years, with 25 percent vesting on August 11, 2027 and the remainder vesting in 36 equal monthly installments over the following three years, subject to continuous employment as of such vesting dates. Olema is providing this information in accordance with Nasdaq Listing Rule 5635(c)(4). About Olema Oncology Olema Oncology is a clinical-stage biopharmaceutical company committed to transforming the standard of care and improving outcomes for patients living with breast cancer and beyond. Olema is advancing a pipeline of novel therapies by leveraging our deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance. Our lead product candidate, palazestrant (OP-1250), is a proprietary, orally available complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD), currently in two Phase 3 clinical trials. In addition, Olema is developing OP-3136, a potent lysine acetyltransferase 6 (KAT6) inhibitor, now in a Phase 1 clinical study. Olema is headquartered in San Francisco and has operations in Cambridge, Massachusetts. For more information, please visit . Media and Investor Relations Contact Courtney O’Konek Vice President, Corporate Communications Olema Oncology media@olema.com ezstandalone.cmd.push(function () { ezstandalone.showAds(131); });

临床1期临床3期高管变更

2026-08-31

·BioSpace

Olema Oncology to Participate in Upcoming September 2026 Investor Conferences

SAN FRANCISCO, Aug. 31, 2026 (GLOBE NEWSWIRE) -- Olema Pharmaceuticals, Inc. (“Olema” or “Olema Oncology”, Nasdaq: OLMA), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of targeted therapies for breast cancer and beyond, today announced that the Company will participate in the following upcoming investor conferences: Citi 2026 Biopharma Back to School Conference Date and Time: September 10, 2026 at 1 p.m. ET Format: Fireside Chat Location: New York, NY Morgan Stanley 24th Annual Global Healthcare Conference Date and Time: September 15, 2026 at 1:50 p.m. ET Format: Fireside Chat Location: New York, NY H.C. Wainwright 28th Annual Global Investment Conference Date and Time: September 16, 2026 at 9:30 a.m. ET Format: Fireside Chat Location: New York, NY Live webcasts and recordings of these presentations will be available, as permitted by the event host, in the Events and Presentations section of Olema’s investor relations website at ir.olema.com . About Olema Oncology Olema Oncology is a clinical-stage biopharmaceutical company committed to transforming the standard of care and improving outcomes for patients living with breast cancer and beyond. Olema is advancing a pipeline of novel therapies by leveraging our deep understanding of endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance. Our lead product candidate, palazestrant (OP-1250), is a proprietary, orally available complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD), currently in two Phase 3 clinical trials. In addition, Olema is developing OP-3136, a potent lysine acetyltransferase 6 (KAT6) inhibitor, now in a Phase 1 clinical study. Olema is headquartered in San Francisco and has operations in Cambridge, Massachusetts. For more information, please visit . Media and Investor Relations Contact Courtney O’Konek Vice President, Corporate Communications Olema Oncology media@olema.com

2026-08-27

·中华乳腺病杂志电子版

专家论坛//组蛋白乙酰转移酶抑制剂在激素受体阳性/HER-2阴性乳腺癌中的研究进展 --谭玉靓，马飞

引文格式谭玉靓，马飞. 组蛋白乙酰转移酶抑制剂在激素受体阳性/HER-2阴性乳腺癌中的研究进展[J/OL]. 中华乳腺病杂志（电子版），2026，20（4）：207-212. DOI：10. 3877/cma. j. issn. 1674-0807. 2026. 04. 002 基金项目国家科技重大专项（2023ZD0502200）作者单位 100021 北京，国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院肿瘤内科通信作者马飞，Email：drmafei@126.com 【摘要】激素受体阳性/HER-2阴性（HR+/HER-2-）乳腺癌是占比最高的乳腺癌亚型，其晚期患者的一线标准治疗为细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）联合内分泌治疗。在后CDK4/6i时代，应用组蛋白乙酰转移酶抑制剂（HATi）是一类全新、有效的表观遗传治疗策略。其中，靶向KAT6A分子的抑制剂通过调节肿瘤细胞的乙酰化及其下游通路，抑制HR+/HER-2-乳腺癌的雌激素信号转导，从而逆转内分泌耐药。本文总结了组蛋白乙酰转移酶在乳腺癌发生发展中的分子机制、HATi治疗HR+/HER-2-乳腺癌的研究进展，探索HATi在HR+/HER-2-乳腺癌中的应用策略和治疗前景。【关键词】乳腺肿瘤；组蛋白乙酰转移酶；激素受体；内分泌治疗全文PDF请点击下载乳腺癌是全球女性发病率最高的恶性肿瘤，严重威胁女性健康。2022年全球共新增230万例乳腺癌病例，占所有癌症病例的25%；乳腺癌导致的死亡病例达67万例，占癌症相关死亡的15. 5%。依据当前的发展趋势，预计到2050年，全球乳腺癌新发病例将达到320万例，死亡病例将达到110万例，分别比2022年增加38%和68%［1］。激素受体（hormone receptor,HR)阳性/HER-2阴性（HR-positive/HER-2-negative，HR+/HER-2-）乳腺癌在所有乳腺癌亚型中占比最高，约为60%。由于ER和/或PR高表达，该亚型通常对内分泌治疗敏感，预后较好［2-3］。晚期患者的一线优选治疗为细胞周期蛋白依赖性激酶4/6抑制剂（cyclindependent kinase 4/6 inhibitor，CDK4/6i）联合内分泌治疗，可显著改善患者的生存结局［4-5］。复发和耐药是HR+/HER-2-乳腺癌患者终身面临的挑战，亟需新的治疗靶点和后续治疗策略。组蛋白乙酰转移酶（histone acetyltransferase，HAT）在表观遗传修饰过程中担任“书写者”，执行组蛋白修饰并充当表观遗传标记［6］。HAT参与多种实体瘤和血液肿瘤的发生发展，是表观遗传学中抗肿瘤药物设计的新兴靶点［7-8］。本文收集和整理 HAT抑制剂（HAT inhibitor，HATi）在抗肿瘤治疗中的作用机制及最新进展，探讨 HATi 在HR+/HER-2-晚期乳腺癌患者中的应用前景。一、HAT在乳腺癌发生发展中的分子机制组蛋白乙酰化和去乙酰化是最常见的组蛋白修饰类型［9-10］，是动态可逆的两个生物过程。HAT催化组蛋白乙酰化，减少染色质压缩并促进转录因子结合，从而使核心组蛋白N端末端赖氨酸残基的ε-氨基乙酰化［11］。去乙酰化由组蛋白去乙酰转移酶（histone deacetylase，HDAC）催化，通过招募共抑制因子，使染色质恢复到转录因子无法进入的紧凑有序的核小体结构状态［12］。HAT家族主要分为4类：GCN5相关氨基乙酰转移酶（GCN5-related N-acetyltransferase，GNAT）、MYST ［包含赖氨酸乙酰转移酶（lysine acetyltransferase，KAT）5、KAT6、KAT7和KAT8］、CREB结合蛋白（CREB-binding protein，CBP）/E1A相关蛋白p300（EP300）和类固醇受体共激活因子（SRC）［13-14］。HAT通过乙酰化多种组蛋白和非组蛋白，参与调节转录控制、细胞衰老、细胞周期和信号转导等过程［15］。 HAT在乳腺癌中既可作为癌基因，也可作为抑癌基因。KAT5是一种单倍体不足肿瘤抑制因子，在部分乳腺癌患者中观察到KAT5的缺失或低表达与不良预后相关［16-17］。另一项研究表明，KAT5的低表达可降低H3K4Ac，进而促进三阴性乳腺癌MDAMB-231异种移植瘤的进展，但该作用在ER+乳腺癌MCF-7异种移植瘤中未观察到［18］。KAT2A、KAT2B、CBP/EP300和KAT6A可募集到ER反应性启动子，对ER阳性（ER-positive，ER+）乳腺癌细胞的雌激素依赖性增殖至关重要［19-21］。KAT6A蛋白的功能发挥基于KAT6A、BRPF1、ING5和MEAF6组成的四聚体复合物。以乙酰辅酶A作为乙酰基供体，KAT6A促进组蛋白（H3K9、H3K14和H3K23）和非组蛋白（p53）的乙酰化，松弛染色质，激活DNA转录（图1）。 KAT6A在乳腺癌中扩增或过表达的频率约为15%，与ER+乳腺癌患者的不良预后相关［10，19］；而KAT6A抑制可诱导H3K23Ac整体和位点特异性表达缺失，下调早期和晚期ER应答相关基因，增强肿瘤细胞内分泌药物敏感性，进而抑制肿瘤细胞的增殖和侵袭［22-23］。在体外实验中，敲低ATF2（GNAT家族）可降低ER+乳腺癌细胞中与内分泌耐药相关基因的表达［24］。SRC是包括ER和PR在内的类固醇激素受体的转录辅激活因子，其中SRC-1和SRC-3促进内分泌治疗抵抗，并以非ER依赖性的方式激活促癌因子［25-27］。以上证据表明，HAT在HR+乳腺癌患者内分泌治疗应答过程中发挥重要作用。二、HATi治疗HR+/HER-2-乳腺癌的研究进展目前开发的HATi主要靶向CBP/EP300和KAT6A/KAT6B［8，10］。CBP/EP300 HATi CPI-1612 和A-485 通过降低ER依赖的基因表达，抑制ER+乳腺癌细胞在体外和体内环境中的生长［28-29］。然而，由于该结构域抑制剂缺乏选择性，临床获益有限。靶向CBP/EP300 BRD虽能改善选择性，但其乙酰化抑制效果不及抑制CBP/EP300 HAT结构域［30］。在ER+乳腺癌中，CBP/EP300 BRD抑制剂GNE-049可下调ER依赖基因的表达和抑制癌细胞的增殖，其抗肿瘤效果与A-485相似［29］。Inobrodib是目前唯一进入1期临床试验的CBP/EP300 BRD抑制剂，试验纳入了乳腺癌患者群体，但其临床前与临床数据尚未披露［8］。 KAT6A/B抑制剂在ER+/HER-2-乳腺癌领域取得了实质性进展。KAT6蛋白的功能发挥基于KAT6A/KAT6B、BRPF1、ING5和MEAF6组成的四聚体复合物。目前，KAT6抑制剂主要作用于KAT6A，涉及PF-07248144、ISM-5043、OP-2、IST-001等。这些小分子KAT6抑制剂通过直接抑制ESR1转录来降低ERα的表达，进而抑制ER信号转导，发挥抗乳腺癌作用［31-34］（图1）。不过目前多数KAT6抑制剂限于临床前研究，仅PF-07248144和OP-3136启动了对应的人体临床试验。 1. PF-07248144 PF-07248144是一种靶向KAT6A和KAT6B的双重抑制剂，以抑制KAT6A为主［35-37］，也是唯一具有1期临床试验结果的KAT6抑制剂（NCT04606446，证据等级ⅡB）。该研究评估了PF-07248144联合氟维司群在CDK4/6i用药后病情进展的ER+/HER-2-晚期乳腺癌患者中的有效性和安全性，涉及CDK4/6i二线治疗（2L）和三线或三线后治疗（3L/3L+）场景［31］。在2L治疗组，中位随访时间为9. 4（7. 2~11. 0）个月，客观缓解率（objective response rate，ORR）为21. 7%，临床获益率（clinical benefit rate，CBR）为43. 5%，未达到中位无进展生存期（progression-free survival，PFS）的终点。在3L/3L+治疗组中，ORR为40. 0%，CBR为60. 0%，中位PFS为10. 7个月。根据现有数据，在CDK4/6i治疗进展后，KAT6抑制剂PF-07248144联合氟维司群策略的生存结局优于其他用药方案，包括CDK4/6i再挑战、PI3K/AKT/mTOR（PAM）通路抑制剂及新型选择性雌激素受体降解剂（selective estrogen receptor degrader, SERD）类药物［38-42］。HR+/HER-2-晚期乳腺癌患者CDK4/6i治疗进展后不同治疗方案的生存结局见表1［31，40，43-51］。在安全性方面，最常见的治疗相关不良反应是味觉障碍（36例，83. 7%），但不涉及三级（G3）或以上事件；其次是中性粒细胞减少（28例，65. 1%）、贫血（18例，41. 9%）和疲劳（18例，41. 9%）。G3或以上事件主要表现为骨髓抑制，发生率为58. 1%（25/43例），包括中性粒细胞减少［G3：18例（41. 9%），G4：1例（2. 3%）］、白细胞减少［G3：5例（11. 6%）］和贫血［G3：4例（9. 3%）］。其中中性粒细胞减少可通过剂量下调得到缓解［31］。以上结果表明，KAT6抑制剂联合内分泌治疗具有良好的抗肿瘤活性和耐受性。期待后续2~3期的临床数据。 2. OP-3136 OP-3136是一种选择性靶向KAT6A和KAT6B的KAT6抑制剂，以抑制KAT6B为主［52］。OP-3136的前体化合物包括OP-1到OP-5，其中OP-2、OP-4和OP-5在临床前研究中显示出良好的抗肿瘤效果。在多个过表达KAT6A的ER+/HER-2-乳腺癌细胞株中，这些化合物可有效抑制细胞增殖，该过程伴随H3K23Ac和ERα表达的抑制。这种现象在ESR1突变的乳腺癌细胞系中也能观察到，提示其可能对内分泌耐药的乳腺癌仍有效。在体内ZR-751乳腺癌异种移植模型中，OP-2、OP-4和OP-5导致剂量依赖性的肿瘤生长抑制和肿瘤消退，并伴有可耐受的体重变化。此外，在T47D细胞中，OP-2+哌柏西利+新型SERD类药物palazestrant表现出剂量依赖性的协同作用，提示了一种全新联合治疗策略［52］。目前，OP-3136已进入针对晚期或转移性实体瘤（包括乳腺癌）的Ⅰ期临床试验（NCT06784193）的招募阶段。三、HATi在HR+/HER-2-乳腺癌的应用策略探索目前的临床前和临床证据提示，KAT6抑制剂是乳腺癌中最具治疗前景的HATi。基于KAT6抑制剂对ER的特异性抑制作用，其主要靶向人群为ER+/HER-2-乳腺癌患者。ctDNA分析表明，相比PIK3CA/PTEN/AKT1突变的患者（n=19），野生型PIK3CA/PTEN/AKT1患者（n=23）接受KAT6抑制剂治疗的ORR（31. 6%比43. 5%）、CBR（47. 4%比56. 5%）和PFS（7. 3个月比13. 7个月）均有改善，但未公布P值。然而，ESR1突变的患者接受KAT6抑制剂治疗的药物反应和生存结局与ESR1野生型相似，其中，ORR为41. 7%和33. 3%、CBR为50. 0%和55. 5%，PFS为10. 7个月和10. 9个月［31］。这提示，携带PIK3CA/PTEN/AKT1突变的患者可能对KAT6抑制剂耐药，而ESR1突变的患者仍然能从KAT6抑制剂的治疗中获益。虽然该结果来源于初步的生物标志物分析，但它为肿瘤专家筛选KAT6抑制剂敏感人群提供了方向。理想的应用策略应为内分泌治疗联合KAT6抑制剂，而不是单药治疗。在目前披露的1期临床试验中，这种联合策略显示出良好的安全性和抗肿瘤疗效。最新证据表明，PF-07248144联合Menin抑制剂在内分泌耐药的ER+乳腺癌临床前模型中具有协同作用，其抗肿瘤疗效与新型SERD类药物艾拉司群相当［23］。这些结果可为后续在目标患者群体中推进该联合治疗策略的开发提供理论支撑。此外，通过新兴化学诱导接近技术开发更精确的HATi，或许可以实现肿瘤特异性转录重编程，进一步扩大HATi的治疗窗口，同时减轻不良反应。在临床前模型中，基于PROTAC的KAT6A靶向药物可明显降解KAT6A［53］。另一种称为乙酰化靶向嵌合体（acetylation targeting chimera，AceTAC）的新技术在KAT3中得到了应用。KAT3通过招募组蛋白乙酰转移酶p300/CBP来乙酰化p53肿瘤抑制蛋白。AceTAC通过与乙酰转移酶的化学定向相互作用，对靶蛋白的乙酰化作用产生精确而直接的影响，从而发挥药理作用［54］。四、结语在乳腺癌生物学背景下，HATi具有良好的治疗潜力，但在药物研发的过程中仍面临挑战。首先，HATi在发挥抗肿瘤活性的同时可能产生一些不良反应，可能成为药物研发的消极因素。虽然KAT6抑制剂PF-07248144在1期临床试验中被认为是可耐受的，但更全面的了解将实现不同靶点抑制模式下疗效和安全性的最佳平衡，以确定最有效、安全的治疗策略。此外，HATi耐药和耐药后的治疗策略也是需要考虑的因素。部分乳腺癌患者在抗肿瘤治疗过程中可出现原发性或继发性耐药。这强调了探索HATi耐药机制的必要性，以识别药物敏感个体，避免原本无反应患者使用后遭受不必要的不良反应。针对HATi耐药相关的基因或通路，有助于开发HATi耐药后治疗策略，其中ctDNA、二代测序技术和空间转录组学等可以提供参考。综上所述，HAT是乳腺癌中极具发展前景的表观遗传靶点，尤其是KAT6A和KAT6B。根据KAT6抑制剂在ER+/HER-2-乳腺癌中的临床数据和临床前数据，笔者推断其有潜力为ER+/HER-2-乳腺癌提供新的治疗策略。随着不良反应的优化管理、新型靶向策略的研发以及耐药后治疗策略的发展，HATi在未来有望造福更多癌症患者。参考文献详见本刊官方网站https://zhrxbzz.cma-cmc.com.cn/CN/1674-0807/home.shtml 版权声明本文为《中华乳腺病杂志（电子版）》原创文章，版权归中华医学会所有。其他媒体、网站、公众号等如需转载本文，请联系本刊编辑委员会获得授权，并在醒目位置标明“原文刊发于《中华乳腺病杂志（电子版）》，卷（期）：起止页码”。

100 项与 Palazestrant 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D12827	-	-	-

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性乳腺癌	临床3期	美国	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	澳大利亚	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	奥地利	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	比利时	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	加拿大	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	捷克	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	法国	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	德国	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	希腊	Olema Pharmaceuticals, Inc.	2025-11-03
ER阳性乳腺癌	临床3期	中国香港	Olema Pharmaceuticals, Inc.	2025-11-03

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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


NCT07085767 (OPERA-02, ASCO2026)	临床3期	ER阳性/HER2阴性乳腺癌一线 ER+ \| HER2-	1,000	Palazestrant plus Ribociclib	遞淵糧顧範觸願艱糧選(糧蓋築願觸蓋夢願襯簾) = 壓積鹹簾廠鹽範製構鬱鏇夢鹽窪艱淵艱顧觸築 (構選壓窪蓋壓網醖鬱餘, 0.59 ~ NR) 更多	积极	2026-05-29
				Letrozole plus Ribociclib	膚築夢獵淵鬱蓋顧築糧(範範範餘餘夢築膚觸簾) = 構獵廠餘積繭簾襯願鏇顧壓繭簾壓築獵鬱糧鬱 (積艱鬱鏇繭襯壓壓鏇襯, 10.1 ~ NR) 更多
NCT06016738 (OPERA-01, Pubmed \| Future Oncol)	临床3期	ER+ \| HER2-	368	Palazestrant	簾襯鑰襯蓋蓋選窪淵鏇(網膚廠壓構蓋鹹簾餘鏇) = 衊繭範餘顧築鏇構選選襯壓願繭夢窪艱壓鏇艱 (齋糧齋製顧鏇鏇鑰糧醖 ) 更多	积极	2025-12-29
				fulvestrant	願蓋憲膚齋觸繭廠願築(顧齋膚憲餘膚構鹹壓窪) = 顧膚鹽製窪構製襯鹽蓋簾鹽夢齋選鏇襯膚壓鏇 (範鹹鏇鹽膚鹽積鏇糧壓, 1 ~ 9) 更多
NCT05508906 (ESMO2025)	临床1/2期	ER阳性/HER2阴性乳腺癌 ER+ \| HER2-	72	Palazestrant 120 mg plus ribociclib	醖鏇構淵淵醖窪襯艱膚(衊構鬱壓製憲鏇鏇鹽網) = 35% 鹽窪築觸範積鏇糧觸顧 (淵鏇觸餘糧繭築糧顧鏇 ) 更多	积极	2025-10-17
				Palazestrant 120 mg plus ribociclib (prior CDK4/6i)
NCT04505826 (phase 1/2 study, Pubmed \| Breast Cancer Res)	临床1/2期	HR阳性乳腺腺癌 \| HER2 阴性乳腺癌 \| HR阳性/HER2阴性乳腺癌 ESR1 mutations	146	Palazestrant 60 mg/day	鹽顧構鏇壓膚醖鑰醖鹹(網醖積觸製蓋衊壓鏇繭) = 25.6% 襯製獵積獵餘鏇選鹹選 (選鏇醖壓獵構簾鏇艱艱 ) 更多	积极	2025-07-01
				Palazestrant 120 mg/day
NCT05508906 (Company_Website) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌一线	63	Palazestrant + Ribociclib	製範糧願鏇繭鬱觸範窪(築餘範膚糧遞廠鬱淵廠) = 獵鬱襯構簾糧觸範衊鑰鏇蓋鹹網選簾網壓衊網 (壓繭窪膚鏇遞簾簾壓網 ) 更多	积极	2024-12-10
				Palazestrant + Ribociclib (prior treatment with a CDK4/6i plus an endocrine therapy)	製範糧願鏇繭鬱觸範窪(築餘範膚糧遞廠鬱淵廠) = 網鹹觸簾襯顧鑰艱憲積鏇蓋鹹網選簾網壓衊網 (壓繭窪膚鏇遞簾簾壓網 ) 更多
NCT05508906 (ESMO_BC2024) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌一线 HER2 Negative \| ER Positive	33	palazestrant+ribociclib	蓋積構製齋選夢築繭範(築醖餘衊選齋選膚窪築) = The most common (≥25%) were nausea, neutropenia (G4: 2 pts; 6%), WBC count decreased, fatigue, anemia, and diarrhea. Most TEAEs were grade 1-2 and consistent with the known safety profiles of each drug. 襯襯憲壓糧鹹鏇構壓壓 (鬱構遞糧獵齋夢齋鑰窪 )	积极	2024-05-16
GlobeNewswire 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 ESR1 Mutation \| ER Positive \| HER2 Negative	46	palbociclib 125 mg+palazestrant 120 mg	齋餘顧獵鬱構艱積願繭(鏇鏇顧糧製鏇襯觸糧鹽) = There was no observed drug-drug interaction between palazestrant and palbociclib, and there was no induced metabolism or increase in exposure of either palbociclib or palazestrant when administered in combination. 觸蓋醖鑰鹽繭齋製衊積 (齋繭網願顧廠憲遞簾窪 ) 更多	积极	2023-12-05
				palbociclib 125 mg+palazestrant 120 mg (ESR1 mutation)
GlobeNewswire 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 HER2 Negative \| ER Positive	19	Ribociclib 600 mg+Palazestrant 120 mg	獵獵遞顧蓋壓範願顧襯(製醖鏇簾簾衊製簾積膚) = well tolerated, with no safety signals or enhancement of toxicity and an overall safety profile remains consistent with the expected safety profile of ribociclib plus an endocrine therapy. 壓憲艱簾鹽製齋壓遞鏇 (築選憲艱糧膚築糧廠顧 ) 更多	积极	2023-12-05
NCT04505826 (ESMO 12023 \| ESMO 22023) 人工标引	临床1/2期	ER阳性/HER2阴性乳腺癌 ER Positive \| HER2 Negative	86	OP-1250 120 mg	獵餘餘蓋選築鹽齋鹽艱(窪鹽觸繭鏇鏇蓋糧憲鹹) = nausea, vomiting, neutropenia, fatigue, headache, constipation, and diarrhea 遞糧顧鏇醖簾選壓憲淵 (繭鹹願製衊醖繭獵窪積 ) 更多	积极	2023-10-22
				OP-1250 120 mg (ESR1 mutation)
NCT04505826 (ENA2022) 人工标引	临床1期	ER阳性/HER2阴性乳腺癌 ER positive \| HER2 negative	37	OP-1250 (60mg)	願醖壓鑰淵願壓範襯選(願蓋簾選選壓簾憲壓餘) = The most common treatment emergent adverse events reported (≥10%) in Phase 1b in the 60 mg/120 mg cohorts were nausea (28%/21%), vomiting (17%/16%), fatigue (17%/5%) and headache (11%/ 11%). 鑰壓襯積積顧獵廠餘憲 (廠鑰齋鏇網鬱淵窪窪鹹 ) 更多	积极	2022-10-28
				OP-1250 (120mg)