Discovery of novel SOS1 inhibitors using machine learning

Affiliations

• Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, Key Laboratory for Carbonaceous Waste Processing and Process Intensification Research of Zhejiang Province, Department of Chemical and Environmental Engineering, The University of Nottingham Ningbo China 199 Taikang East Road Ningbo 315100 P. R. China Jianfeng.Ren@nottingham.edu.cn Bencan.Tang@nottingham.edu.cn.
• Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zuchongzhi Road 201203 Shanghai China hxie@simm.ac.cn.
• University of Chinese Academy of Sciences No.19A Yuquan Road Beijing 100049 China.
• School of Mathematics, Watson Building, University of Birmingham Edgbaston Birmingham B15 2TT UK.
• Faculty of Medicine and Health Sciences, University of Nottingham (Malaysia Campus) Semenyih 43500 Malaysia.
• School of Chemistry, University of Nottingham University Park Nottingham NG7 2RD UK jonathan.hirst@nottingham.ac.uk.
• Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Zhongshan Tsuihang New District Zhongshan 528400 China.

PMID: 38665844 DOI: PMC11042245 DOI: 10.1039/d4md00063c

Abstract

Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50value in the proximity of 20 μg mL-1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented byCL01545365occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors.

Keywords:Hepatocellular carcinoma; INTS family; Immune infiltration; Prognosis; Transcription.

References

• Moore A. R. Rosenberg S. C. McCormick F. Malek S. Nat. Rev. Drug Discovery. 2020;19:533–552. doi: 10.1038/s41573-020-0068-6.
• Punekar S. R. Velcheti V. Neel B. G. Wong K.-K. Nat. Rev. Clin. Oncol. 2022;19:637–655. doi: 10.1038/s41571-022-00671-9.
• Cox A. D. Fesik S. W. Kimmelman A. C. Luo J. Der C. J. Nat. Rev. Drug Discovery. 2014;13:828–851. doi: 10.1038/nrd4389.
• Papke B. Der C. J. Science. 2017;355:1158–1163. doi: 10.1126/science.aam7622.
• McCormick F. Clin. Cancer Res. 2015;21:1797–1801. doi: 10.1158/1078-0432.CCR-14-2662.