LSZ-102(LSZ-102) - 药物靶点：ERα_专利_临床

概要

基本信息

药物类型

小分子化药

别名

LSZ 102、LSZ102

靶点

ERα

作用方式

降解剂

作用机制

ERα 降解剂(雌激素受体α 降解剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病

在研适应症-

非在研适应症

ER阳性乳腺癌

原研机构

Novartis AG

在研机构-

非在研机构

Novartis Pharmaceuticals Corp.

权益机构-

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C25H17F3O4S

InChIKeySJXNPGGVGZXKKI-NYYWCZLTSA-N

CAS号2135600-76-7

关联

1

项与 LSZ-102 相关的临床试验

NCT02734615

/ Terminated临床1期

A Phase I/Ib, Open Label Study of LSZ102 Single Agent and LSZ102 in Combination With Either LEE011 (LSZ102 + LEE011) or BYL719 (LSZ102 + BYL719) in Patients With Advanced or Metastatic ER+ Breast Cancer Who Have Progressed After Endocrine Therapy

To characterize the safety and tolerability, identify recommended doses and regimens for future studies, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of LSZ102 as a single agent and in combination with either LEE011 or BYL719 in adult patients with locally advanced or metastatic ER+ breast cancer who have progressed after endocrine therapy.

开始日期2016-06-14

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 LSZ-102 相关的临床结果

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100 项与 LSZ-102 相关的转化医学

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100 项与 LSZ-102 相关的专利（医药）

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13

项与 LSZ-102 相关的文献（医药）

2023-02-23·Journal of medicinal chemistry1区 · 医学

Research Progress on Bioactive Metal Complexes against ER-Positive Advanced Breast Cancer

1区 · 医学

Review

作者: Liu, Wukun ; Liu, Lijuan ; Lu, Yunlong ; Zhou, Yanyu ; Liang, Zhenlin

Breast cancer is the most prevalent cancer in women and represents a serious disease that is harmful to life and health. In 1977, with the approval of tamoxifen, endocrine therapy has become the main clinical treatment for ER-positive (ER+) breast cancer. Although patients initially respond well to endocrine therapies, drug resistance often emerges and side effects can be challenging. To overcome drug resistance, the exploration for new drugs is a priority. Metal complexes have demonstrated significant antitumor activities, and platinum complexes are widely used in the clinic against various cancers, including breast cancer. In this Perspective, the first section describes the classification and mechanism of endocrine therapy drugs for ER+ breast cancer, and the second section summarizes research since 2000 into metal complexes with activity toward ER+ breast cancer. Finally, we discuss the opportunities, challenges, and future directions for metal complexes in the treatment of ER+ breast cancer.

2022-04-14·Journal of medicinal chemistry1区 · 医学

Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability

1区 · 医学

Article

作者: Cao, Yangzhi ; Zhang, Dan ; Meng, Xin ; Lu, Zhengyu ; Yang, Yushe ; Guo, Bin ; Kong, Deyu

Endocrine therapies in the treatment of early and metastatic estrogen receptor α positive (ERα+) breast cancer (BC) are greatly limited by de novo and acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization of LSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led us to identify compound 40 as the preferred candidate. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.

2022-01-02·Xenobiotica; the fate of foreign compounds in biological systems4区 · 医学

Species-dependent hepatic and intestinal metabolism of selective oestrogen receptor degrader LSZ102 by sulphation and glucuronidation

4区 · 医学

Article

作者: Gunduz, Mithat ; Walles, Markus ; Baldoni, Daniela ; Ji, Yan ; Birlinger, Bertrand-Luc ; Romeo, Andrea ; Jin, Yi ; Schiller, Hilmar ; Pearson, David

LSZ102 is an orally bioavailable selective oestrogen receptor degrader in clinical development for the treatment of breast cancer. Preclinical studies showed efficacy in xenograft models on oral dosing. However, oral bioavailability was relatively low in several preclinical species (7-33%), and was associated with first-pass metabolism, particularly intestinal first-pass.To investigate metabolism and first-pass effects, metabolites were analysed in human plasma samples after oral dosing of LSZ102 to patients, rat plasma samples after oral dosing of [¹⁴C]LSZ102, and in vitro incubations of [¹⁴C]LSZ102 with human and rat hepatocytes and intestinal S9 fractions. The kinetics of human sulfotransferase (SULT) enzymes potentially involved in metabolism of LSZ102 was characterised.Sulphate metabolites were found to be the major components in human plasma, as well as in human hepatocytes and intestinal S9 fractions. Contrastingly, glucuronidation was predominant in rat plasma, hepatocytes and intestinal S9. LSZ102 was found to be metabolised by several human SULTs expressed in liver and intestine. The combined metabolism data in rat and human provide supporting evidence for an extensive intestinal first-pass metabolism effect via sulphation in human but glucuronidation in rat.As LSZ102 is metabolised by a number of different SULTs, drug-drug interactions resulting from the inhibition of one SULT are unlikely.Despite the observed species difference in metabolism, the major human metabolites of LSZ102, sulphate M5, glucuronide M4, and secondary glucuronide/sulphate metabolite M12, have no or weak pharmacological activity and are not considered a toxicity risk as they are phase II conjugative metabolites.

1

项与 LSZ-102 相关的新闻（医药）

2023-02-03

·生物制药小编

口服SERD冲破迷雾

去年，两家大药企在ER+/HER2-乳腺癌连环失败，再度令口服SERD开发者们望而止步，粉身碎骨的赛诺菲最终洒泪宣布退出赛道。不过，最近Stemline的Elacestrant（Orserdu）成功获批一扫阴霾，口服SERD开发久违的望见了第一丝希望。2023年1月27日，Stemline Therapeutics的口服SERD抑制剂Elacestrant获得FDA加速批准上市（商品名为Orserdu)，成为FDA批准的首款口服SERD，用于治疗ER+/HER2-/ESR1突变的晚期转移性乳腺癌。Elacestrant的获批是基于一项Ⅲ期临床数据EMERALD，相比于对照组，Elacestrant将ER+/HER2-晚期转移性乳腺癌的mPFS从1.9个月延长到3.8个月，疾病进展或死亡风险降低45%。SERD药物地位奠定临床上，乳腺癌患者通常按照激素受体HR（雌激素受体ER和孕激素受体-PR）和HER2分型进行治疗。其中ER+/HER2-型乳腺癌是最常见的亚型，约占总体乳腺癌的70%。作为一种性激素依赖性癌症，内分泌疗法是ER+/HER2-型乳腺癌最常用的治疗手段之一，包括雌激素受体调节剂（SERM）和芳香化酶抑制剂（AI)。不过，经过该类药物治疗的患者中出现相当高比列的复发。据统计，约有50%的患者在2~5年内会病情复发。SERD药物被认为是解决HR+型乳腺癌内分泌耐药的一种新的治疗手段。在内分泌治疗耐药的HR+乳腺癌患者中，雌激素受体1（ESR1）基因突变是其最常见的耐药机制。SERD抑制剂主要是通过与癌细胞表面的ER相结合，降低ER的稳定性，诱导其被细胞正常的蛋白降解机制降解，降低ER水平，从而抑制癌细胞的生长。而且，与抑制剂雌激素活性的调节剂不同，SERD理论上通过介导ER的降解，能够更为全面地抑制ER的功能，并有可能解决ER突变产生的耐药。抑制和降解ER受体双重机制的开发前景，令SERD（雌激素受体降解剂）抑制剂的开发逐渐受到大药企们的关注。在Elacestrant之前，Fulvestrant是唯一获批上市的SERD药物。2002年，Fulvestrant的获批让SERD机制立于ER+乳腺癌内分泌疗法之列。虽然Fulvestrant作用机制佳，但受制于成药特征，Fulvestrant只能肌肉注射给药，导致剂量问题而不能发挥更大的疗效，其患者便利性和生物利用度被大大限制了。因此，SERD的口服药成为多家巨头目前最主要的开发方向。开发之路布满荆棘不过，口服SERD抑制剂研发难度之大已经埋葬不少大药企的研发管线。除了早年在临床早期就浅尝辄止的阿斯利康、诺华之外，去年赛诺菲和罗氏两家领先玩家相继在此领域折臂。阿斯利康的AZD-9496，最早于2014年进入临床阶段，最后一次更新的时间为2021年8月25日，接下来再无消息，销声匿迹。诺华的LSZ-102，最早于2016年进入临床阶段，最后一次更新信息的时间为2021年10月11日，试验终止。恒瑞医药的SHR9549，最早于2018年进入临床阶段（CTR20181130），最后一次更新信息的时间为2019年10月14日，试验终止。这是最早一批倒在SERD研发路上的企业。几年之后，赛诺菲、罗氏也再次相继折在这个领域。2022年3月，赛诺菲口服SERD抑制剂Amcenestrant单药二线治疗ER+/HER2-乳腺癌患者的Ⅱ期临床AMEERA-3宣告失败。之后8月中旬赛诺菲再次宣布，Amcenestrant联用Palbociclib治疗一线ER+/HER2-乳腺癌患者的Ⅲ期临床AMEERA-5中期分析无法达到临床终点。为此，赛诺菲丧失了继续开发口服SERD的信心，公司宣布停止Amcenestrant全部的开发工作。除赛诺菲之外，罗氏口服SERD抑制剂也遭受了挫折。2022年4月，罗氏宣布其口服SERD抑制剂giredestrantⅡ期临床试验acelERA未达到改善PFS的主要终点。但罗氏并未因为这次失败而砍掉Giredestrant管线。目前，Giredestrant仍在开展多项III期研究。而在赛诺菲、罗氏之后，口服SERD罕见的传来了好消息。2022年10月26日，阿斯利康宣布其口服SERD抑制剂camizestrant在一项II期试验成功，该临床达到了改善无进展生存期（PFS）的主要终点。小编总结在赛诺菲，罗氏两家大药企相继挑战失败，令口服SERD蒙上阴霾，Elacestrant的成功获批力挽狂澜，为口服SERD的开发注入了一剂强心剂，阿斯利康camizestrant的Ⅱ临床成功消息也一定程度鼓舞了士气。目前Fulvestranti已即将面临专利到期，这是一个等待口服SERD大展身手的领域。参考出处：https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancerSanofi折臂SERD“绞肉机”/空之客SERD：Big Pharma的噩梦，Biotech的坟场/丰硕研究

临床3期上市批准临床2期加速审批临床失败

100 项与 LSZ-102 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15362

研发状态

10 条进展最快的记录,

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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1期	美国	Novartis Pharmaceuticals Corp.	2016-06-14
ER阳性乳腺癌	临床1期	日本	Novartis Pharmaceuticals Corp.	2016-06-14
ER阳性乳腺癌	临床1期	比利时	Novartis Pharmaceuticals Corp.	2016-06-14
ER阳性乳腺癌	临床1期	法国	Novartis Pharmaceuticals Corp.	2016-06-14
ER阳性乳腺癌	临床1期	德国	Novartis Pharmaceuticals Corp.	2016-06-14
ER阳性乳腺癌	临床1期	意大利	Novartis Pharmaceuticals Corp.	2016-06-14
ER阳性乳腺癌	临床1期	新加坡	Novartis Pharmaceuticals Corp.	2016-06-14

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临床结果

适应症

分期

评价

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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


NCT02734615 (Pubmed \| Clin Cancer Res)	临床1期	ER阳性乳腺癌	198	LSZ102 alone	繭顧鏇顧願淵範願範窪(鑰觸夢餘餘鹽蓋鏇餘壓) = The most common AEs were gastrointestinal 範糧廠壓選選獵獵鬱襯 (鏇憲淵餘鑰範願鹽簾憲 ) 更多	-	2021-08-25
NCT02734615 (Pubmed \| Clin Cancer Res)	临床1期	ER阳性乳腺癌	198	LSZ102 with ribociclib		-	2021-08-25
PD7-09 (SABCS2020)	临床1期	ER阳性乳腺癌 estrogen receptor-positive	76	LSZ102 + Ribociclib	壓鹹壓淵願積鹽艱淵齋(鹹鏇衊艱構艱廠壓繭簾) = 31.6% 繭襯蓋窪鏇窪獵淵獵糧 (蓋範醖繭鹽餘衊糧廠蓋 ) 更多	积极	2020-02-15