Design of Orally-bioavailable Tetra-cyclic phthalazine SOS1 inhibitors with high selectivity against EGFR

Huan He; Ruiqi Chen; Ziwei Wang; Luolong Qing; Yu Zhang; Yi Liu; Weidong Pan; Huaxiang Fang; Silong Zhang

doi:10.1016/j.bioorg.2023.106536

Design of Orally-bioavailable Tetra-cyclic phthalazine SOS1 inhibitors with high selectivity against EGFR

Bioorg Chem. 2023 Jul:136:106536. doi: 10.1016/j.bioorg.2023.106536. Epub 2023 Apr 10.

Authors

Huan He¹, Ruiqi Chen², Ziwei Wang², Luolong Qing², Yu Zhang², Yi Liu³, Weidong Pan⁴, Huaxiang Fang⁵, Silong Zhang⁶

Affiliations

¹ School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China; Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan 430200, PR China.
² Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China.
³ Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China; School of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan 430023, PR China; Hubei Key Laboratory of Radiation Chemistry and Functional Materials, Hubei University of Science and Technology, Xianning 437100, PR China.
⁴ School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China. Electronic address: wdpan@163.com.
⁵ Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China. Electronic address: fang_huaxiang@whyxpharma.com.
⁶ School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China; Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan 430200, PR China. Electronic address: silongzhang@whu.edu.cn.

PMID: 37054529
DOI: 10.1016/j.bioorg.2023.106536

Abstract

KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many deadliest cancers. Son of sevenless homolog 1 (SOS1) is a crucial regulator of KRAS to modulate KRAS from inactive to active states. We previously discovered tetra-cyclic quinazolines as an improved scaffold for inhibiting SOS1-KRAS interaction. In this work, we report the design of tetra-cyclic phthalazine derivatives for selectively inhibiting SOS1 against EGFR. The lead compound 6c displayed remarkable activity to inhibit the proliferation of KRAS(G12C)-mutant pancreas cells. 6c showed a favorable pharmacokinetic profile in vivo, with a bioavailability of 65.8% and exhibited potent tumor suppression in pancreas tumor xenograft models. These intriguing results suggested that 6c has the potential to be developed as a drug candidate for KRAS-driven tumors.

Keywords: EGFR; KRAS; Protein–protein interaction; SOS1; Tetra-cyclic phthalazine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ErbB Receptors / genetics
Humans
Mutation
Proto-Oncogene Proteins p21(ras)* / genetics
Quinazolines / pharmacology
SOS1 Protein* / genetics
SOS1 Protein* / metabolism

Substances

SOS1 Protein
Proto-Oncogene Proteins p21(ras)
Quinazolines
ErbB Receptors
EGFR protein, human