PO.CH01.01 · 化学

EGFR-PROTAC分子TY-2719减弱对第三代EGFR TKI的获得性耐药并增强KRAS突变体抑制剂在实体瘤中的疗效

The EGFR-PROTAC molecule TY-2719 attenuates acquired resistance to 3rd-generation EGFR TKIs and augments the efficacy of KRAS mutant inhibitors in solid tumors

编号 5171 展板 21 时间 4/21 09:00–12:00 区域 Section 39 主讲 Shengli Dong, PhD

分会场 Targeted Protein Degradation and Induced Proximity

该海报暂无可下载的资料 AACR 官方页面

作者与单位 Authors & Affiliations

Apeng Liang*,#, Shengli Dong*,#, Shaoqing Chen*, Hongqiang Li, Zhiyong He, Zhengfei Guo, Meihua Li, Shunxun Han, Guangbin Liu, Xi Wang, Yanyan Liu, Ling Fang, Yi Long, Xiang Zhang, Wei Wu, Chengshan Niu, Jun Li, Yusheng Wu

TYK Medicines, Inc., Changxing, Zhejiang, China

摘要 Abstract

中文摘要

引言：对EGFR-TKI的获得性耐药是非小细胞肺癌（NSCLC）临床管理中的一项重大挑战。TY-2719是由通用医药（TYK Medicines）开发的一种有效的口服广谱EGFR-PROTAC，旨在克服与第三代EGFR-TKI相关的耐药。TY-2719不仅表现出出色的安全性特征，还增强了KRAS突变体抑制剂在NSCLC和胰腺导管腺癌（PDAC）模型中的疗效。结果：TY-2719有效降解了NSCLC H3255细胞中携带L858R突变的EGFR，以及BaF3细胞中携带L858R/T790M/C797S和19del/C797S突变的EGFR。然而，它不降解表达野生型EGFR的细胞（如A549和H358细胞）中的EGFR。它对EGFR突变体表现出出色的抗增殖活性，但不抑制正常细胞（包括NHEK、MCF-10A、IOSE-80和FHC细胞）的生长。TY-2719在BaF3 L858R/C797S和BaF3 del19/C797S CDX小鼠模型中克服了奥希替尼耐药，并增强了Divarasib（GDC-6036）和泛KRASi Daroxonrasib（RMC-6236）在NSCLC H1972和H2122细胞中的疗效，以及Daroxonrasib在MiaPaca 2（PDAC，KRAS G12D）、AsPC-1、SU.86.86、PANC-1（PDAC，KRAS G12D）和Capan-1（PDAC，KRAS G12V）中的疗效。EGFR-TKI（包括奥希替尼）的常见副作用是由于正常组织中野生型EGFR被抑制而导致的皮肤反应和腹泻。TY-2719的DMPK特性出色，在Sprague-Dawley大鼠实验中具有更优的毒性特征。经过三周治疗后，100 mg/kg（mpk）TY-2719治疗组与载体组之间，雄性和雌性大鼠的体重均无差异。接受100 mg/kg TY-2719治疗的大鼠也未观察到腹泻。在BN Norway雌性大鼠皮疹实验中，28天后，37.5 mpk吉非替尼对照组的所有大鼠均出现明显的皮疹症状，而在TY-2719 100 mpk组中，所有大鼠的皮肤均表现正常。同时，与载体组相比，100 mpk TY-2719治疗对Norway大鼠的体重无显著影响。综上所述，我们鉴定出一种强效且安全的EGFR-PROTAC分子，它可能为克服NSCLC患者对第三代EGFR TKI的耐药性提供新的治疗机会，并增强KRAS突变体抑制剂在NSCLC和PDAC中的疗效。 #Shengli Dong和Apeng Liang对本工作贡献相同。 * 通讯作者。

查看英文原文 English abstract

Introduction: Acquired resistance to EGFR-TKIs poses a significant challenge in the clinical management of non-small-cell lung cancer (NSCLC). TY-2719, an effective oral, broad-spectrum EGFR-PROTAC developed by TYK Medicines, was designed to overcome the resistance associated with third-generation EGFR-TKIs. TY-2719 not only demonstrated an excellent safety profile but also enhanced the efficacy of KRAS mutant inhibitors in NSCLC and pancreatic ductal adenocarcinoma (PDAC) models. Results: TY-2719 effectively degraded EGFR with the L858R mutation in NSCLC H3255 cells and the L858R/T790M/C797S and 19del/C797S mutations in BaF3 cells. However, it did not degrade EGFR in cells expressing wild-type EGFR, such as A549 and H358 cells. It demonstrated excellent antiproliferative activity against EGFR mutants but did not inhibit the growth of normal cells, including NHEK, MCF-10A, IOSE-80, and FHC cells. TY-2719 overcame osimertinib resistance in BaF3 L858R/C797S and BaF3 del19/C797S CDX mouse models and enhanced the efficacy of Divarasib (GDC-6036) and pan-KRASi Daroxonrasib (RMC-6236) in NSCLC H1972 and H2122 cells, as well as Daroxonrasib in MiaPaca 2 (PDAC, KRAS G12D), AsPC-1, SU.86.86, PANC-1 (PDAC, KRAS G12D), and Capan-1 (PDAC KRAS G12V). Common side effects of EGFR-TKIs, including osimertinib, are skin reactions and diarrhea due to wild-type EGFR inhibition in normal tissues. The DMPK characteristics of TY-2719 were excellent, with superior toxicity profiles in Sprague-Dawley rat experiments. The body weights of male and female rats showed no difference between the 100 mg/kg (mpk) TY-2719 treated group and the vehicle group after three weeks of treatment. No diarrhea was observed in rats treated with 100 mg/kg TY-2719, either. In the BN Norway female rat rash experiment, after 28 days, all rats in the 37.5 mpk gefitinib control group showed obvious rash symptoms, whereas in the TY-2719 100 mpk group, all rats' skin appeared normal. Meanwhile, treatment with 100 mpk TY-2719 had no significant effect on the body weight of Norway rats compared to that of the vehicle group.Taken together, we have identified a potent and safe EGFR-PROTAC molecule which may grant new therapeutic opportunities to overcome drug resistance of 3rd -generation EGFR TKIs in NSCLC patients and enhance the efficacy of KRAS mutant inhibitors in NSCLC and PDAC. #Shengli Dong and Apeng Liang contributed equally to this work. * Correspondence authors.

利益披露 Disclosure

A. Liang*,#, TYK Medicines, Inc. Employment, Stock Option, Patent. S. Dong*,#, TYK Medicines, Inc. Employment, Stock Option, Patent. S. Chen*, TYK Medicines, Inc. Employment, Stock Option, Patent. H. Li, TYK Medicines, Inc. Employment. Z. He, TYK Medicines, Inc. Employment. Z. Guo, TYK Medicines, Inc. Employment. M. Li, TYK Medicines, Inc. Employment, Stock Option, Patent. S. Han, TYK Medicines, Inc. Employment, Patent. G. Liu, TYK Medicines, Inc. Employment, Patent. X. Wang, TYK Medicines, Inc. Employment. Y. Liu, TYK Medicines, Inc. Employment. L. Fang, TYK Medicines, Inc. Employment. Y. Long, TYK Medicines, Inc. Employment, Patent. X. Zhang, TYK Medicines, Inc. Employment. W. Wu, TYK Medicines, Inc. Employment, Stock Option. C. Niu, TYK Medicines, Inc. Employment, Stock Option, Patent. J. Li, TYK Medicines, Inc. Employment, g., Board of Directors, non-salaried role), Stock Option, Patent. Y. Wu, TYK Medicines, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Stock Option, Other Business Ownership, ), Patent, Trademark, Copyright, Other Intellectual Property.

← 返回 AACR 2026 检索