bims-pimaco 2023-10-08 papers

Eur J Med Chem. 2023 Sep 25. pii: S0223-5234(23)00795-X. [Epub ahead of print]261 115828

Inhibition of Son of Sevenless Homologue 1 (SOS1): Promising therapeutic treatment for KRAS-mutant cancers.

Tingkai Chen, Xu Tang, Zhenqi Wang, Feng Feng, Chunlei Xu, Qun Zhao, Yulan Wu, Haopeng Sun, Yao Chen.

Kristen rat sarcoma (KRAS) is one of the most common oncogenes in human cancers. As a guanine nucleotide exchange factor, Son of Sevenless Homologue 1 (SOS1) represents a potential therapeutic concept for the treatment of KRAS-mutant cancers because of its activation on KRAS and downstream signaling pathways. In this review, we provide a comprehensive overview of the structure, biological function, and regulation of SOS1. We also focus on the recent advances in SOS1 inhibitors and emphasize their binding modes, structure-activity relationships and pharmacological activities. We hope that this publication can provide a comprehensive compendium on the rational design of SOS1 inhibitors.

Keywords: Cancer therapy; KRAS; PROTACs; SOS1 inhibitors; Small molecules

DOI: https://doi.org/10.1016/j.ejmech.2023.115828

Cancer Discov. 2023 Oct 06. OF1

Hyperactivation of Oncogenic Pathways Hinders Cancer Cell Survival.

Gain-of-function screens reveal the context-specific lethality of oncogenic pathway activation.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-158

Front Oncol. 2023 ;13 1252516

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer.

Lindor Qunaj, Michael S May, Alfred I Neugut, Benjamin O Herzberg.

KRAS G12C mutations are critical in the pathogenesis of multiple cancer types, including non-small cell lung (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal (CRC) cancers. As such, they have increasingly become a target of novel therapies in the management of these malignancies. However, the therapeutic success of KRAS G12C inhibitors to date has been far more limited in CRC and PDAC than NSCLC. In this review, we briefly summarize the biochemistry of KRAS targeting and treatment resistance, highlight differences in the epidemiology of various G12C-mutated cancers, and provide an overview of the published data on KRAS G12C inhibitors for various indications. We conclude with a summary of ongoing clinical trials in G12C-mutant CRC and a discussion of future directions in the management of this disease. KRAS G12C mutation, targeted therapies, colorectal cancer, non-small cell lung cancer, pancreatic cancer, drug development.

Keywords: KRAS G12C mutation; colorectal cancer; drug development; non-small cell lung cancer; pancreatic cancer; targeted therapies

DOI: https://doi.org/10.3389/fonc.2023.1252516