Side Chain Investigation of Imidazopyridazine as a Hinge Binder for Targeting Actionable Mutations of RET Kinase

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-09-03 DOI:10.1021/acsmedchemlett.4c0028710.1021/acsmedchemlett.4c00287

Arunkranthi Maturi, Kasinathuni Naga Visweswara Sastry, Surendra Kumar, Vinay Pogaku, Hyun Jin Kwon, Sung-Min Ahn and Mi-hyun Kim*,

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引用次数: 0

Abstract

Actionable mutations of RET kinase have been identified as oncogenic drivers of solid tumors, including thyroid cancer, metastatic colorectal cancer, and nonsmall cell lung cancer. Although multikinase inhibitors and RET selective inhibitors are used to treat patients with RET alterations, there is insufficient research addressing certain issues: which actionable mutations arise from these therapies, how to improve the clinical response rate to RET inhibitors, and how to design new inhibitors to overcome drug resistance. Therefore, the development of sophisticated tool compounds is required to investigate the molecular mechanisms of actionable mutations and to develop breakthrough therapeutics for different RET alterations. Herein, we present our investigation into the side chains of imidazopyridazine hinge binders that are capable of inducing protein–ligand interaction patterns from the gatekeeper to the waterfront regions. Extending the substituents at the second and sixth positions enhanced the IC₅₀ up to < 0.5 nM for diverse RET alterations.

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将咪唑哒嗪作为铰链粘合剂用于靶向 RET 激酶可作用突变的侧链研究

RET 激酶的可作用突变已被确定为实体瘤（包括甲状腺癌、转移性结直肠癌和非小细胞肺癌）的致癌因素。虽然多激酶抑制剂和 RET 选择性抑制剂被用于治疗 RET 基因改变的患者，但目前还没有足够的研究来解决某些问题：这些疗法会产生哪些可作用突变，如何提高 RET 抑制剂的临床反应率，以及如何设计新的抑制剂来克服耐药性。因此，需要开发复杂的工具化合物来研究可作用突变的分子机制，并针对不同的 RET 改变开发突破性疗法。在此，我们介绍了我们对咪唑并哒嗪铰链结合剂侧链的研究，这些侧链能够诱导从守门员到滨水区的蛋白质-配体相互作用模式。在第二和第六个位置扩展取代基，可将不同 RET 改变的 IC50 提高到 < 0.5 nM。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.