Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jmedchem.4c01531
Robert L Hudkins ₁ , Eric Allen ₁ , Alexandra Balcer ₁ , Isaac D Hoffman ₁ , Samhita Iyer ₁ , Melissa Neal ₁ , Kirk J Nelson ₁ , Marc Rideout ₁ , Qing Ye ₁ , Jacqueline H Starrett ₁ , Piyush Patel ₁ , Todd Harris ₁ , Ronald V Swanson ₁ , Daniel C Bensen ₁

Affiliation

Activating FGFR3 alterations have been identified in up to 15–20% of muscle-invasive bladder cancer and metastatic urothelial carcinoma (mUC), and as high as 80% in nonmuscle invasive bladder cancers. FGFR3 germline mutations have also been associated with a variety of skeletal dysplasias. Achondroplasia, the most common form of dwarfism in humans, results from a G380R mutation in FGFR3. The pan-FGFR inhibitor erdafitinib was approved for the treatment of mUC with FGFR3 alterations but is limited due to FGFR isoform off-target toxicities and the development of on-target gatekeeper resistance mutations. TYRA-300 (22) was conceived using a structure-based approach as a potent FGFR3-selective inhibitor to avoid the toxicities associated with inhibition of FGFR1, FGFR2, and FGFR4, and to be agnostic for the FGFR3 gatekeeper mutations. TYRA-300 is being evaluated in a Phase 1 clinical trial in urothelial cancers and solid tumors, with intention to initiate Phase 2 studies in urothelial cancers and achondroplasia.

中文翻译：

TYRA-300 的发现：首个用于治疗尿路上皮癌和软骨发育不全的口服选择性 FGFR3 抑制剂

在高达 15-20% 的肌层浸润性膀胱癌和转移性尿路上皮癌（mUC）中已发现激活 FGFR3 改变，在非肌层浸润性膀胱癌中高达 80%。FGFR3 种系突变也与多种骨骼发育不良有关。软骨发育不全是人类最常见的侏儒症，由 FGFR3 中的 G380R 突变引起。泛 FGFR 抑制剂厄达替尼被批准用于治疗具有 FGFR3 改变的 mUC，但由于 FGFR 亚型脱靶毒性和靶向守门人耐药突变的发展而受到限制。TYRA-300 （22）使用基于结构的方法构想为一种有效的 FGFR3 选择性抑制剂，以避免与抑制 FGFR1、FGFR2 和 FGFR4 相关的毒性，并且与 FGFR3 守门人突变无关。TYRA-300 正在尿路上皮癌和实体瘤的 1 期临床试验中进行评估，旨在启动尿路上皮癌和软骨发育不全的 2 期研究。

更新日期：2024-09-11

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南