BAY-1436032(BAY-1436032) - 药物靶点：IDH1_在研适应症：晚期恶性实体瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

IDH1

作用方式

抑制剂

作用机制

IDH1抑制剂(细胞质异柠檬酸脱氢酶[NADP]抑制剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构-

权益机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

结构/序列

分子式C26H30F3N3O3

InChIKeyRNMAUIMMNAHKQR-QFBILLFUSA-N

CAS号1803274-65-8

关联

2

项与 BAY-1436032 相关的临床试验

NCT03127735

/ Completed临床1期

An Open-label, Non-randomized, Multicenter Phase I Study to Determine the Maximum Tolerated and / or Recommended Phase II Dose of Oral Mutant IDH1 (mIDH1) Inhibitor BAY1436032 and to Characterize Its Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Clinical Efficacy in Patients With mIDH1-R132X Advanced Acute Myeloid Leukemia (AML)

To determine the maximum tolerated and / or recommended Phase II dose of oral mutant IDH1 (mIDH1) inhibitor BAY1436032 and to characterize its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy in patients with mIDH1-R132X advanced acute myeloid leukemia (AML)

开始日期2017-06-14

申办/合作机构

Bayer AG

NCT02746081

/ Completed临床1期

An Open-label, Non-randomized, Multicenter Phase I Study to Determine the Maximum Tolerated or Recommended Phase II Dose of Oral Mutant IDH1 Inhibitor BAY1436032 and to Characterize Its Safety, Tolerability, Pharmacokinetics and Preliminary Pharmacodynamic and Anti-tumor Activity in Patients With IDH1-R132X-mutant Advanced Solid Tumors

The primary objective of this study is:
- Determine the safety, tolerability, maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) of BAY 1436032 in patients with isocitrate dehydrogenase-1 (IDH1)-R132X-mutant advanced solid tumors.
The secondary objectives of this study are:
* Evaluate the pharmacokinetics (PK) of BAY1436032 in patients with IDH1-R132X-mutant advanced solid tumors.
* Evaluate the effect of a standard high-fat, high calorie meal on the PK of BAY1436032.
* Assess pharmacodynamic (PD) effects and evidence of clinical efficacy associated with BAY1436032 administration in patients with IDH1-R132X-mutant advanced solid tumors.

开始日期2016-05-26

申办/合作机构

Bayer AG

100 项与 BAY-1436032 相关的临床结果

登录后查看更多信息

100 项与 BAY-1436032 相关的转化医学

登录后查看更多信息

100 项与 BAY-1436032 相关的专利（医药）

登录后查看更多信息

15

项与 BAY-1436032 相关的文献（医药）

2023-04-13·Journal of medicinal chemistry1区 · 医学

Differentiating Inhibition Selectivity and Binding Affinity of Isocitrate Dehydrogenase 1 Variant Inhibitors.

1区 · 医学

Article

作者: Liu, Shuang ; Mikhailov, Victor ; Abboud, Martine ; Reinbold, Raphael ; Schofield, Christopher J. ; Liu, Xiao

Isocitrate dehydrogenase (IDH) 1/2 gain-of-function variants catalyze the production of the oncometabolite 2-hydroxyglutarate and are validated targets for leukemia treatment. We report binding and inhibition studies on 13 IDH1/2 variant inhibitors, including clinical candidates and drugs, with wild-type (wt) IDH1 and its cancer-associated variant, IDH1 R132H. Interestingly, all the variant inhibitors bind wt IDH1 despite not, or only weakly, inhibiting it. Selective inhibition of the IDH1 R132H variant over wt IDH1 does not principally relate to the affinities of the inhibitors for the resting forms of the enzymes. Rather, the independent binding of Mg²⁺ and 2-oxoglutarate to the IDH1 variant makes the variant more susceptible to allosteric inhibition, compared to the tighter binding of the isocitrate-Mg²⁺ complex substrate to wt IDH1. The results highlight that binding affinity need not correlate with inhibition selectivity and have implications for interpretation of inhibitor screening results with IDH and related enzymes using turnover versus binding assays.

2023-01-01·Neuro-Oncology Advances

Monitoring response to a clinically relevant IDH inhibitor in glioma—Hyperpolarized 13C magnetic resonance spectroscopy approaches

Article

作者: Minami, Noriaki ; Wu, Jing ; Ronen, Sabrina M ; Kim, Yaewon ; Cherukuri, Murali Krishna ; Swenson, Rolf E ; Mushti, Chandrasekhar ; Hong, Donghyun ; Vigneron, Daniel B

AbstractBackgroundMutant isocitrate dehydrogenase (IDHmut) catalyzes 2-hydroxyglutarate (2HG) production and is considered a therapeutic target for IDHmut tumors. However, response is mostly associated with inhibition of tumor growth. Response assessment via anatomic imaging is therefore challenging. Our goal was to directly detect IDHmut inhibition using a new hyperpolarized (HP) 13C magnetic resonance spectroscopy-based approach to noninvasively assess α-ketoglutarate (αKG) metabolism to 2HG and glutamate.MethodsWe studied IDHmut-expressing normal human astrocyte (NHAIDH1mut) cells and rats with BT257 tumors, and assessed response to the IDHmut inhibitor BAY-1436032 (n ≥ 4). We developed a new 13C Echo Planar Spectroscopic Imaging sequence with an optimized RF pulse to monitor the fate of HP [1-13C]αKG and [5-12C,1-13C]αKG with a 2.5 × 2.5 × 8 mm3 spatial resolution.ResultsCell studies confirmed that BAY-1436032-treatment leads to a drop in HP 2HG and an increase in HP glutamate detectable with both HP substrates. Data using HP [5-12C,1-13C]αKG also demonstrated that its conversion to 2HG is detectable without the proximal 1.1% natural abundance [5-13C]αKG signal. In vivo studies showed that glutamate is produced in normal brains but no 2HG is detectable. In tumor-bearing rats, we detected the production of both 2HG and glutamate, and BAY-1436032-treatment led to a drop in 2HG and an increase in glutamate. Using HP [5-12C,1-13C]αKG we detected metabolism with an signal-to-noise ratio of 23 for 2HG and 17 for glutamate.ConclusionsOur findings point to the clinical potential of HP αKG, which recently received FDA investigational new drug approval for research, for noninvasive localized imaging of IDHmut status.

2021-05-15·Clinical Cancer Research1区 · 医学

Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors

1区 · 医学

Article

作者: Kaulfuss, Stefan ; Munhoz, Catya ; Peña, Carol ; Heinemann, Volker ; Langer, Simon ; Janku, Filip ; Jeffers, Michael ; Rentzsch, Christine ; Chawla, Sant P. ; Roggia, Cristiana ; Rohrberg, Kristoffer ; Bähr, Oliver ; Reschke, Susanne ; Steinbach, Joachim P. ; Lenz, Heinz-Josef ; Wagner, Markus ; Sankhala, Kamalesh K. ; Burger, Michael C. ; Narita, Yoshitaka ; Wick, Antje ; Schiff, David ; Wenger, Katharina ; Ikeda, Masafumi ; Cai, Charles ; Schuler, Martin ; Lassen, Ulrik ; Wick, Wolfgang ; Genvresse, Isabelle ; Tabatabai, Ghazaleh ; Lagkadinou, Eleni ; Ando, Yuichi

AbstractPurpose:BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.Patients and Methods:The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors.Results:In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.Conclusions:BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

100 项与 BAY-1436032 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床1期	德国	Bayer AG	2016-05-26
晚期恶性实体瘤	临床1期	丹麦	Bayer AG	2016-05-26
晚期恶性实体瘤	临床1期	日本	Bayer AG	2016-05-26
晚期恶性实体瘤	临床1期	美国	Bayer AG	2016-05-26
急性髓性白血病	药物发现	德国	Bayer AG	2017-06-14
急性髓性白血病	药物发现	美国	Bayer AG	2017-06-14

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03127735 (Pubmed \| Leukemia) 人工标引	临床1期	急性髓性白血病 IDH1 Mutation	27	BAY1436032	(觸網壓蓋艱製積遞鹹鬱) = not identified 積醖膚築蓋觸網觸衊壓 (繭構鏇衊願鑰廠餘淵鬱 )	不佳	2020-11-01
EHA2020	临床1期	IDH1突变急性髓性白血病	27	BAY1436032	(餘顧鹽鏇鑰壓憲鏇製範) = 33% 衊淵餘願鑰鹹窪鏇艱膚 (鹹願繭壓憲鏇醖鏇願鏇 ) 更多	积极	2020-05-14
AACR2016	临床1期	-	-	BAY 1436032	蓋蓋壓範網膚襯膚壓壓(製構壓構窪製鑰獵襯網) = 構構積簾獵夢繭蓋餘構獵選壓鹹觸構夢築範壓 (壓積網鹹顧觸鹹壓選糧 )	积极	2016-07-15