更新于：2024-11-01

Tyrosine kinase x TYK2 x c-Kit

更新于：2024-11-01

基本信息

关联

项与 Tyrosine kinase x TYK2 x c-Kit 相关的药物

IDRX-42

靶点

TYK2 x c-Kit

作用机制

TYK2抑制剂 [+2]

在研机构

Aptuit (Verona) Srl [+3]

原研机构

Merck KGaA

在研适应症

胃肠道间质瘤 [+3]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 Tyrosine kinase x TYK2 x c-Kit 相关的临床试验

CTR20230641 / Not yet recruiting临床1期

一项在转移性和/或不可切除的胃肠道间质瘤 (GIST) 受试者中进行的 IDRX-42 首次人体 (FIH) 研究

I 期主要： · 确定转移性和/或手术不可切除的 GIST 受试者的 IDRX-42 最大耐受剂量 (MTD) 和/或 II 期临床试验推荐剂量和时间表 (RP2DS) 次要： · 评估 IDRX-42 的安全性和耐受性 · 描述 IDRX-42 的药代动力学 (PK) 概况特性 · 评估 IDRX-42 的初步抗肿瘤活性探索性： · 探索潜在的预测性和/或药效学标志物 · 评估 KIT、PDGFRA 和其他相关基因突变等位基因片段的变化及其与临床结局的相关性 Ib 期主要： · 进一步描述 IDRX-42 在转移性和/或手术不可切除的 GIST 受试者中的安全性和耐受性特性 · 评估 IDRX-42 在转移性和/或手术不可切除的 GIST 受试者中的抗肿瘤活性次要： · 进一步评估 IDRX-42 的初步抗肿瘤活性 · 描述 IDRX-42 的药代动力学概况特性探索性： · 探索潜在的预测性和/或药效学标志物 · 评估 KIT、PDGFRA 和其他相关基因突变等位基因片段的变化及其与临床结局的相关性

开始日期-

申办/合作机构

Aptuit (Verona) Srl

[+2]

NL-OMON53904 / RecruitingN/A

A first-in-human (FIH) study of IDRX-42 in participants with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) - StrateGIST 1

开始日期2024-05-27

申办/合作机构

IDRx, Inc.初创企业

NCT05489237 / Recruiting临床1期

A First-in-human (FIH) Study of IDRX-42 in Participants With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) [Study ID: StrateGIST 1]

This is the first clinical trial of IDRX-42. The study is designed to evaluate the safety, tolerability, PK, and preliminary antitumor activity of IDRX-42 in adult participants with advanced (metastatic and/or surgically unresectable) GIST.

开始日期2022-08-01

申办/合作机构

IDRx, Inc.初创企业

100 项与 Tyrosine kinase x TYK2 x c-Kit 相关的临床结果

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100 项与 Tyrosine kinase x TYK2 x c-Kit 相关的转化医学

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0 项与 Tyrosine kinase x TYK2 x c-Kit 相关的专利（医药）

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项与 Tyrosine kinase x TYK2 x c-Kit 相关的文献（医药）

2020-06-01·American Journal of Medical Genetics Part A

KIT‐related piebaldism in a Chinese girl

作者: Huang, Yu‐Qi ; Chen, Yong‐Feng ; Zhong, Wei ; Yang, Chao ; Zhang, Qi ; Zhu, Lei ; Xu, Wen‐Cong

AbstractPiebaldism is a rare, autosomal dominant and congenital pigmentary disorder characterized by stable depigmentation of the skin and white forelock. Mutations in KIT or SNAI2 genes result in piebaldism. Most individuals with piebaldism have a family history of the disorder. Herein, we report a 5‐month‐old Chinese girl with severe piebaldism but no family history thereof. She has white forelock and large patches of depigmentation in the jaw, central anterior trunk, perineum and extremities. We performed whole‐exome and Sanger sequencing and identified a de novo KIT mutation (NM_000222.2: c.2657G>A, p.Gly886Val) in exon 18 of KIT in the proband. Currently, this mutation is located in the most extreme C‐terminal of the tyrosine kinase domain 2 of the KIT gene amongst all reported mutations and causes a severe clinical phenotype. We further reviewed literature on piebaldism and summarized 79 KIT gene mutations that lead to this disease. Our study may expand knowledge on the genotype–phenotype correlation in piebaldism and serve as a reference for genetic counseling and prenatal diagnosis of affected families.

2008-05-01·Blood1区 · 医学

Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia

1区 · 医学

Article

作者: Tomasson, Michael H. ; Heath, Sharon ; Graubert, Timothy A. ; Lubman, Olga ; Wilson, Richard K. ; Ries, Rhonda E. ; Fremont, Daved H. ; Nagarajan, Rakesh ; Shannon, William D. ; Bloomfield, Clara D. ; Westervelt, Peter ; Walgren, Richard ; Mardis, Elaine R. ; Walter, Matthew J. ; Watson, Mark ; Link, Daniel C. ; Baty, Jack ; DiPersio, John F. ; Payton, Jacqueline E. ; McLellan, Michael D. ; Xiang, Zhifu ; Kasai, Yumi ; Ley, Timothy J. ; Zhao, Yu ; Miner, Tracie

AbstractActivating mutations in tyrosine kinase (TK) genes (eg, FLT3 and KIT) are found in more than 30% of patients with de novo acute myeloid leukemia (AML); many groups have speculated that mutations in other TK genes may be present in the remaining 70%. We performed high-throughput resequencing of the kinase domains of 26 TK genes (11 receptor TK; 15 cytoplasmic TK) expressed in most AML patients using genomic DNA from the bone marrow (tumor) and matched skin biopsy samples (“germline”) from 94 patients with de novo AML; sequence variants were validated in an additional 94 AML tumor samples (14.3 million base pairs of sequence were obtained and analyzed). We identified known somatic mutations in FLT3, KIT, and JAK2 TK genes at the expected frequencies and found 4 novel somatic mutations, JAK1V623A, JAK1T478S, DDR1A803V, and NTRK1S677N, once each in 4 respective patients of 188 tested. We also identified novel germline sequence changes encoding amino acid substitutions (ie, nonsynonymous changes) in 14 TK genes, including TYK2, which had the largest number of nonsynonymous sequence variants (11 total detected). Additional studies will be required to define the roles that these somatic and germline TK gene variants play in AML pathogenesis.

2008-03-01·The Journal of Pathology1区 · 医学

Knock‐in murine models of familial gastrointestinal stromal tumours

1区 · 医学

Article

作者: Gunawan, B

AbstractIn recent years, gastrointestinal stromal tumour (GIST) has emerged from a poorly understood group of mesenchymal tumours to a distinct pathological entity that has become a leading model for new therapies targeting kinases. GIST pathogenesis is driven by receptor tyrosine kinase‐activating mutations most often in KIT or PDGFRA that may be sporadic or result in familial GIST syndromes. In a recent issue of The Journal of Pathology (J Pathol 2008;214:302–311), Nakai and colleagues report that mutation of the previously un‐modelled tyrosine kinase II domain of KIT generates a spectrum of features very similar to that in two human GIST families. Knock‐in mouse models of GIST may prove extremely useful in pre‐clinical evaluation of kinase‐targeted compounds and of the mechanism of drug resistance, but intriguingly it now seems clearer that the distribution of GIST in mouse models and humans is different. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

项与 Tyrosine kinase x TYK2 x c-Kit 相关的新闻（医药）

2024-08-07

·Pharmaceutical Technology

IDRx raises $120m to fund gastric tumour trials for lead TKI therapy

In 2022, IDRx raised $122m in Series A financing and licensed two TKI inhibitors – IDRX-42 from Merck KGaA, and IDRX-73 from Blueprint Medicines. Image credit: Mr.Boyz / Shutterstock. US-based precision therapeutics company IDRx has raised $120m in a Series B financing round to fund the clinical development of its lead oncology candidate, IDRX-42. The preferred stock financiers included multiple US investment companies such as RA Capital Management, Commodore Capital, and Blackstone Multi-Asset Investing. The company plans to use the proceeds to finance the ongoing Phase I trial and start a pivotal trial evaluating the therapy in patients with gastrointestinal stromal tumours (GIST). IDRX-42 is a selective tyrosine kinase inhibitor (TKI). IDRx licensed the therapy from Merck KGaA in 2022. It has received an orphan drug designation for the treatment of GIST from the US Food and Drug Administration (FDA). The ongoing Phase I StrateGIST 1 trial (NCT05489237) is evaluating the safety and tolerability of IDRX-42 in patients with metastatic and/or surgically unresectable GIST after the failure of Novartis ’ Gleevec/Glivec (imatinib mesylate) and other approved drugs. In June, the company reported positive preliminary data from the study showing a 23% objective response rate (ORR) across all patients who received a median of four prior lines of therapy. An ORR of 43% was seen in patients receiving IDRX-42 as a second-line treatment, of which all were partial responses. See Also: Takeda’s ADZYNMA gains EU approval for cTTP treatment Amneal’s CREXONT gains FDA approval for Parkinson’s treatment Commonly observed side effects were Grade I gastrointestinal symptoms. Three out of the 63 patients experienced dose-limited toxicities, which were resolved, and patients elected to reduce dosages. IDRx’s pipeline also consists of another TKI, IDRX-73, which the company licensed from Blueprint Medicines . TKIs have been effective in treating various cancers. AstraZeneca ‘s Tagrisso (osimertinib) is approved for treating non-small cell lung cancer and generated $5.8bn in sales last year, as per the company’s financials. Gleevec/Glivec is a top 20 highest-grossing drug for Novartis, and raked in $561m in sales in 2023, as per the company’s financials. It has not been smooth sailing for all TKIs. In October 2023, Takeda Pharmaceutics issued a voluntary withdrawal of Exkivity (mobocertinib) in the US after a confirmatory Phase III trial failed to meet its primary endpoint.

临床1期临床结果上市批准孤儿药临床3期

2024-06-14

·医药笔记

自免创新药出海后续看点有哪些？

▎Armstrong 2024年6月13日，明济生物宣布将临床前TL1A抗体的全球权益授权给艾伯维，艾伯维支付1.5亿美元预付款和近期里程碑付款，以及15.6亿美元里程碑金额，两位数比例的销售分成。很长时间以来，国产创新药出海大部分集中在肿瘤领域，其他一些则主要是新药物形式，如小核酸、CAR-T等。自免药物在美国市场异常火热，但国产自免药物出海仍属罕见，诺诚健华BTK抑制剂授权给Biogen用于多发性硬化，但后被退回。Biohaven的透脑JAK1/TYK2授权给Biohaven。海思科的TYK2授权给Alumis，后者刚刚申请纳斯达克IPO。恒瑞医药长效TSLP抗体授权给Aiolos，后者被GSK以14亿美元收购。加上此次明济生物长效TL1A的高额出海交易，或许意味着国产自免创新药的出海潮即将来临。国内的自免，高度聚焦于Th2、Th17通路，差异化产品相对较少。聚焦自免的biotech包括康诺亚、荃信生物、智翔金泰、三生国健、鑫康合生物、洛启生物等。康诺亚的管线包括IL-4R（全球首款拿下过敏性鼻炎）、TSLP、CD38、MASP-2等，荃信生物的管线包括IL-17、IL-4R、IL-23、IFNAR1、TSLP、IL-33、KIT等。智翔金泰的管线包括IL-17、IL-4R、TSLP、IFNAR1等。三生国健的管线包括IL-17、IL-5、IL-4R、IL-1β、IL-33等，非自免管线刚刚转给三生制药，更加聚焦于自免。鑫康合核心管线为IL-17A/F抗体，也是国内唯一，与丽珠合作开发。洛启生物管线包括TSLP、IL-4R，采用纳米抗体形式，通过吸入给药，具有明显的差异化特色。荣昌生物的泰它西普为全球首个上市的TACI-Fc，在美国SLE进入三期临床。不过这一赛道的首个高额交易来自Vertex 49亿美元并购Alpine，具有高亲和力的优势，IgA肾病今年下半年进入三期临床。康方生物的管线包括IL-4R、IL-17等，后续差异化的管线还有IL-4R/ST2双抗，自免双抗也是如今MNC关注的终点，强生前不久两起并购都针对自免双抗。自免双抗终，融捷康的IL-4R/IL-5、科越医药和天辰生物的补体双功能分子都已经进入临床阶段。头部企业中，恒瑞医药布局了IL-17、IL-4R、IL-5、TSLP、MASP-2等，百济神州BTK抑制剂主攻膜性肾病来切入自免，后续还有TYK2抑制剂、IRAK4 PROTAC（该赛道先驱为Kymera，与赛诺菲合作开发）等。诺诚健华BTK多个自免适应症同步推进。信达生物布局了IL-23，后续的自免管线重点是OX40L、CD40L，与赛诺菲的突变点类似。差异化的产品还有再鼎医药的外用IL-17，已经进入二期临床阶段。总结虽然此前也有高光、海思科、恒瑞医药的自免新药出海，但交易金额相比于同期的肿瘤药等尚不算高，此次明济生物临床前TL1A抗体的高额交易，或预示着国产自免创新药的出海热潮即将来临。 Armstrong技术全梳理系列 GPRC5D靶点全梳理； CD40靶点全梳理； CD47靶点全梳理；补体靶向药物技术全梳理；补体药物：眼科治疗的重要方向； Claudin 6靶点全梳理； Claudin 18.2靶点全梳理；靶点冷暖，行业自知；中国大分子新药研发格局；被炮轰的“me too”；佐剂百年史；胰岛素百年传奇； CUSBEA：风雨四十载；中国新药研发的焦虑；中国生物医药企业的研发竞争；中国双抗竞争格局；中国ADC竞争格局；中国双抗技术全梳理；中国ADC技术全梳理； Ambrx技术全梳理； Vir Biotech技术全梳理； Immune-Onc技术全梳理；亘喜生物技术全梳理；康哲药业技术全梳理；科济药业技术全梳理；恺佧生物技术全梳理；同宜医药技术全梳理；百奥赛图技术全梳理；腾盛博药技术全梳理；创胜集团技术全梳理；永泰生物技术全梳理；中国抗体技术全梳理；德琪医药技术全梳理；德琪医药技术全梳理2.0；和铂医药技术全梳理；荣昌生物技术全梳理；再鼎医药技术全梳理；药明生物技术全梳理；恒瑞医药技术全梳理；豪森药业技术全梳理；正大天晴技术全梳理；吉凯基因技术全梳理；基石药业技术全梳理；百济神州技术全梳理；百济神州技术全梳理第2版；信达生物技术全梳理；信达生物技术全梳理第2版；中山康方技术全梳理；复宏汉霖技术全梳理；先声药业技术全梳理；君实生物技术全梳理；嘉和生物技术全梳理；志道生物技术全梳理；道尔生物技术全梳理；尚健生物技术全梳理；康宁杰瑞技术全梳理；科望医药技术全梳理；科望医药技术全梳理2.0；岸迈生物技术全梳理；礼进生物技术全梳理；康桥资本技术全梳理；余国良的抗体药布局；荃信生物技术全梳理；安源医药技术全梳理；三生国健技术全梳理；仁会生物技术全梳理；乐普生物技术全梳理；同润生物技术全梳理；宜明昂科技术全梳理；派格生物技术全梳理；迈威生物技术全梳理； Momenta技术全梳理； NGM技术全梳理；普米斯生物技术全梳理；普米斯生物技术全梳理2.0；三叶草生物技术全梳理；贝达药业抗体药全梳理；泽璟制药抗体药全梳理；恒瑞医药抗体药全梳理；齐鲁制药抗体药全梳理；石药集团抗体药全梳理；豪森药业抗体药全梳理；华海药业抗体药全梳理；科伦药业抗体药全梳理；百奥泰技术全梳理；凡恩世技术全梳理。

免疫疗法临床3期并购细胞疗法临床2期

2024-05-30

·精准药物

药物筛选中心（暨南大学）对外提供新药筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶、HDAC、COX、GPCR、报告基因、病毒、细菌等筛选模型，能够开展肿瘤、神经系统疾病、心脑血管病、糖尿病、病毒和细菌感染性疾病等领域相关靶标、细胞、机制的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型1）蛋白水平：激酶：Abl, ABL(M351T), ABL(H396P), ABL(Y253F), ABL1 (E255K), ABL1 (G250E), ABL(Q252H), AKT1, AKT2, AKT3, ALK, ALK5, AuroraA, AuroraB, AXL, BRAF, BRAF(V599E), BTK, DDR1, DDR2, EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M), Flt3, FLT3(D835Y), FGFR1, FGFR2, FGFR3, FGFR4, Her2, Her4, KIT, MET, IGF-1R, FGFR1, JAK1, JAK2, JAK3, MAPK10, MAPK14, mTOR, TrkA, TrkB, TrkC,TYK2, KDR, SRC, PDGFRa, PDGFRA(D842V), PDGFRb, RET, ZAK。蛋白酶：MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, MMP-14, ADAM5, ADAM10, ADAMTS13, TACE/ADAM17, Furin, Cathepsin E, Cathepsin D, BACE-1, DDP4, DDP8, DDP9, HIV protease-1, PMVII，PMVIV。HDACs：HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, Sirt1, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6。2）肿瘤细胞活性：近500种肿瘤细胞系；基于Ba/F3的耐药模型3）抗病毒/菌药物筛选：EV71和HSV病毒活性筛选模型；金黄色葡萄球菌、大肠杆菌和沙门氏杆菌等4）体内药效：移植瘤模型对外服务1）体外活性筛选（单剂量抑制率；多剂量IC50）；2）体内药效；3）机制研究；4）药代动力学研究；5）化合物工艺优化、大量订制。咨询合作

临床1期