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

• Published in: Bioorganic chemistry Vol. 136; p. 106536
• Main Authors: He, Huan, Chen, Ruiqi, Wang, Ziwei, Qing, Luolong, Zhang, Yu, Liu, Yi, Pan, Weidong, Fang, Huaxiang, Zhang, Silong
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.07.2023; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; EGFR; ErbB Receptors - genetics; Humans; KRAS; Life Sciences & Biomedicine; Mutation; Physical Sciences; Protein–protein interaction; Proto-Oncogene Proteins p21(ras) - genetics; Quinazolines - pharmacology; Science & Technology; SOS1; SOS1 Protein - genetics; SOS1 Protein - metabolism; Tetra-cyclic phthalazine; KRAS; Tetra-cyclic phthalazine; SOS1; Protein–protein interaction; EGFR; SON; RAS; Protein -protein interaction
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106536

[Display omitted] •Six tetra-cyclic phthalazine derivatives were designed and synthesized for Selectively disrupting SOS1:KRAS protein–protein interaction against EGFR.•6c showed a favorable pharmacokinetic profile in vivo, with a bioavailability of 65.8% and exhibited potent tumor suppression in pancreas tumor xenograft models.•Preclinical evaluation of cardiac toxicity suggested that the potential cardiovascular safety risk of 6c on heart death will be a concern at a high dosage. 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.