Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRASG12C

Cuicui Li; Ni Zhao; Luyan An; Zhen Dai; Xiaoyi Chen; Fan Yang; Qidong You; Bin Di; Chi Hu; Lili Xu

doi:10.1016/j.apsb.2021.06.013

Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS^G12C

Acta Pharm Sin B. 2021 Sep;11(9):2670-2684. doi: 10.1016/j.apsb.2021.06.013. Epub 2021 Jun 25.

Authors

Cuicui Li^{1

2}, Ni Zhao^{1

2}, Luyan An^{1

2}, Zhen Dai^{1

2}, Xiaoyi Chen^{1

2}, Fan Yang^{1

2}, Qidong You¹, Bin Di^{1

2}, Chi Hu³, Lili Xu^{1

2}

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
² Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
³ Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 211198, China.

Abstract

Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health. Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying 80% of all lung cancer subtypes. Except for other mutations (e.g., KRAS ^G12V/D ) that are also vital for the occurrence, KRAS ^G12C gene mutation is a significant driving force of NSCLC, with a prevalence of approximately 14% of all NSCLC patients. However, there are only a few therapeutic drugs targeting KRAS^G12C mutations currently. Here, we synthesized hydrocarbon-stapled peptide 3 that was much shorter and more stable with modest KRAS^G12C binding affinity and the same anti-tumor effect based on the α-helical peptide mimic SAH-SOS1_A. The stapled peptide 3 effectively induced G2/M arrest and apoptosis, inhibiting cell growth in KRAS-mutated lung cancer cells via disrupting the KRAS-mediated RAF/MEK/ERK signaling, which was verified from the perspective of genomics and proteomics. Peptide 3 also exhibited strong anti-trypsin and anti-chymotrypsin abilities, as well as good plasma stability and human liver microsomal metabolic stability. Overall, peptide 3 retains the equivalent anti-tumor activity of SAH-SOS1_A but with improved stability and affinity, superior to SAH-SOS1_A. Our work offers a structural optimization approach of KRAS^G12C peptide inhibitors for cancer therapy.

Keywords: Cell-cycle arrest and apoptosis; KRASG12C; Non-small cell lung cancer; Stability; Stapled peptides.