9TK2

SOS1 IN COMPLEX WITH COMPOUND 3

これはPDB形式変換不可エントリーです。

9TK2 の概要

• エントリーDOI: 10.2210/pdb9tk2/pdb
• 分子名称: Son of sevenless homolog 1, ~{N}6-methyl-~{N}2-[(1~{R})-1-phenylethyl]pyridine-2,6-dicarboxamide (3 entities in total)
• 機能のキーワード: regulatory protein, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57659.96

構造登録者

Breed, J. (登録日: 2025-12-08, 公開日: 2026-06-24, 最終更新日: 2026-07-22)

主引用文献

Bagal, S.K.,Diene, C.R.N.,Stefanovic-Barrett, S.,Breed, J.,Kauffman, G.W.,Bodnarchuk, M.S.,Collie, G.W.,Staniszewska, A.D.,Srivastava, A.,Irving, E.,Cassar, D.J.,Gray, S.,Hughes, C.,Kettle, J.G.,Nash, S.,Northall, S.,Peter, A.,Schade, M.,Stubbs, C.J.,Smith, A.,Young, L.
Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers.
J.Med.Chem., 69:15277-15293, 2026

PubMed Abstract: Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kp. Multiple analogues were progressed into PK/PD studies where they were combined with a KRAS inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRAS inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.

PubMed: 42301273
DOI: 10.1021/acs.jmedchem.5c03800

実験手法

X-RAY DIFFRACTION (1.924 Å)