Novel stapled peptides serving as KRASG12C/SOS1 inhibitor and application of novel stapled peptide

Abstract

The invention discloses novel stapled peptides serving as a KRASG12C / SOS1 inhibitor and application of the novel stapled peptides. Also provided are a composition comprising these stapled peptides anda method for using such peptides in the treatment of cancers. The stapled peptides are more stable in alpha-helical conformation to some extent; the stapled peptides are higher in affinity with KRASG12C protein; the enzymolysis capability of resisting trypsin and alpha-chymotrypsin is better; besides, the plasma stability of the stapled peptides is greatly enhanced, and the stapled peptides are derived from an alpha-helical binding region of SOS1 protein and KRAS protein and inhibit the activation of the KRAS protein. The invention also relates to a preparation method of the novel stapled peptides, a pharmaceutical composition containing these stapled peptides, and application of the stapled peptides independently used or in combination with other compounds for the prevention or treatmentof cancers (such as non-small cell lung cancer).

Description

technical field [0001] The present invention relates to a staple peptide, which is derived from the α-helix binding region of SOS1 protein and KRAS protein. Background technique [0002] Lung cancer is the main cause of cancer death in the world (Cheng and Planken 2018), which seriously endangers human life and health. In the past few decades, the treatment of lung cancer has received great attention (Wang, Huang et al. 2019). Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases (Jemal, Bray et al.2011), and the Ras proto-oncogene is the most frequently mutated gene in NSCLC (Prior, Lewis et al.2012, Li, Liu et al. 2018), mutations were detected in approximately 25% of all tumors (de Castro Carpeno and Belda-Iniesta 2013), and the v-Ki-ras2Kirsten rat sarcoma virus oncogene (KRAS) accounted for 90% of RAS mutations in lung adenocarcinomas (John C. Hunter and Sudershan Gondi2015, Rothschild2015). Most oncogenic forms of RAS impair their intrinsic GTP...

AI Technical Summary

Problems solved by technology

However, after the polypeptide fragment leaves the overall structure of the protein, it will not be able to stably form the secondary structure required for binding, but will easily form a random coil conformation, resulting in a decrease in binding activity, and it is more susceptible to degradation by peptidases, so it cannot be directly used as a drug.

Elizaveta S. Leshchinera et al. designed and synthesized SAH-SOS1A with the sequence Ac-RRFFGIXLTNXLKTEEGN-NH 2 , X stands for (S)-α-methyl-α-pentenylglycine (S5) (Leshchiner, Parkhitko et al.2015), but for the development of peptide drugs, too long sequences often lead to reduced solubility , poor stability, increased production costs and other issues, so most of the listed peptide drugs are about 10 amino acids in length

[0005] Despite the in-depth understanding of the mechanism of KRAS and its pathological mutations, the study of effective and stable targeted drugs for KRAS mutations is still far away and remains a daunting challenge

Images