bims-pimaco 2023-10-15 papers

Nat Commun. 2023 Oct 12. 14(1): 6422

Oncogenic context shapes the fitness landscape of tumor suppression.

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

DOI: https://doi.org/10.1038/s41467-023-42156-y

Clin Cancer Res. 2023 Oct 13.

A small molecule with big impact: MRTX1133 targets the KRASG12D mutation in pancreatic cancer.

Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier.

KRAS mutations driver oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDAC have KRAS mutations, with G12D (~42% of cases) and G12V (~32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, non-covalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent in vitro and in vivo antitumor efficacy against KRASG12D-mutant cancer cells, especially in PDAC, leading to its recent initiation of a phase I/II clinical trial. Here, we provide a summary of the recent advancements related to the use of MRTX1133 for treating KRASG12D-mutant PDAC, focusing on its efficacy and underlying mechanistic actions. Additionally, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bring about a paradigm shift in its management.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-2098

J Med Chem. 2023 Oct 11.

Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition.

Murat Kücükdisli, Hassen Bel-Abed, Davide Cirillo, Wen-Ting Lo, Nina-Louisa Efrém, André Horatscheck, Liudmila Perepelittchenko, Polina Prokofeva, Theresa A L Ehret, Silke Radetzki, Martin Neuenschwander, Edgar Specker, Guillaume Médard, Susanne Müller, Stephanie Wilhelm, Bernhard Kuster, Jens Peter von Kries, Volker Haucke, Marc Nazaré.

Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure-activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors called PITCOINs. Cocrystal structures and docking experiments supported the rationalization of the structural determinants essential for inhibitor activity and high selectivity. Profiling of PITCOINs in a panel of more than 118 diverse kinases showed no off-target kinase inhibition. Notably, by addressing a selectivity pocket, PITCOIN4 showed nanomolar inhibition of PI3K-C2α and >100-fold selectivity in a general kinase panel. Our study paves the way for the development of novel therapies for diseases related to PI3K-C2α function.

DOI: https://doi.org/10.1021/acs.jmedchem.3c01319