Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

Yating Chen; Qiupei Liu; Xianghui Meng; Wenxu Cao; Lihui Duo; Xiaorong Song; Xiangchun Shen; Sze Shin Low; Wan Yong Ho; Bencan Tang; Pengli Zhang; Hua Xie; Guoqin Xia

doi:10.1016/j.bmcl.2025.130282

Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

Yating Chen, Qiupei Liu, Xianghui Meng, Wenxu Cao, Lihui Duo, Xiaorong Song, Xiangchun Shen, Sze Shin Low, Wan Yong Ho, Bencan Tang, Pengli Zhang, Hua Xie, Guoqin Xia

Faculty of Science and Engineering

Research output: Journal Publication › Article › peer-review

Abstract

The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could downregulate the levels of phosphorylated ERK and AKT in the NCI-H358 cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven cancer.

Original language	English
Article number	130282
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	125-126
DOIs	https://doi.org/10.1016/j.bmcl.2025.130282
Publication status	Published - 1 Sept 2025

Keywords

KRAS mutation
Resistance
SOS1 inhibitor
SOS1-KRAS interaction

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2025.130282

Cite this

@article{cdc7d3ddf2314cbf8f764f89ca6a7c51,

title = "Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers",

abstract = "The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could downregulate the levels of phosphorylated ERK and AKT in the NCI-H358 cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven cancer.",

keywords = "KRAS mutation, Resistance, SOS1 inhibitor, SOS1-KRAS interaction",

author = "Yating Chen and Qiupei Liu and Xianghui Meng and Wenxu Cao and Lihui Duo and Xiaorong Song and Xiangchun Shen and Low, {Sze Shin} and Ho, {Wan Yong} and Bencan Tang and Pengli Zhang and Hua Xie and Guoqin Xia",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Ltd",

year = "2025",

month = sep,

day = "1",

doi = "10.1016/j.bmcl.2025.130282",

language = "English",

volume = "125-126",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd.",

}

TY - JOUR

T1 - Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

AU - Chen, Yating

AU - Liu, Qiupei

AU - Meng, Xianghui

AU - Cao, Wenxu

AU - Duo, Lihui

AU - Song, Xiaorong

AU - Shen, Xiangchun

AU - Low, Sze Shin

AU - Ho, Wan Yong

AU - Tang, Bencan

AU - Zhang, Pengli

AU - Xie, Hua

AU - Xia, Guoqin

PY - 2025/9/1

Y1 - 2025/9/1

N2 - The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could downregulate the levels of phosphorylated ERK and AKT in the NCI-H358 cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven cancer.

AB - The development of small molecular inhibitors to target the guanine nucleotide exchange factor SOS1 has been proved to be a hopeful strategy for the treatment of various KRAS-driven cancers. Constructing novel SOS1 inhibitors is urgently needed due to the increasing drug resistance arising from structural similarity of earlier analogs. Herein, we discovered a new SOS1 inhibitor with para-dimethylaminoazetidine quinazoline scaffold. The most potent compound 10i showed superior activity to the reported SOS1 inhibitor Hit 1 in both the KRASG12C::SOS1 PPI inhibition assay and 3D proliferation inhibitory assay, and compound 10i presented enhanced aqueous solubility under physiologically relevant pH 6.8. Moreover, compound 10i could downregulate the levels of phosphorylated ERK and AKT in the NCI-H358 cancer cell line. Overall, these studies showed that 10i was a promising drug candidate for the treatment of KRAS-driven cancer.

KW - KRAS mutation

KW - Resistance

KW - SOS1 inhibitor

KW - SOS1-KRAS interaction

UR - http://www.scopus.com/inward/record.url?scp=105005425436&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2025.130282

DO - 10.1016/j.bmcl.2025.130282

M3 - Article

AN - SCOPUS:105005425436

SN - 0960-894X

VL - 125-126

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

M1 - 130282

ER -

Design and structural optimization of novel SOS1 inhibitors in KRAS-driven cancers

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this