Targeting K-Ras, Pak-1, And Mcl-1 for the Treatment of Cancer

Abstract

Malignant cancers are the second leading cause of death in the United States, with a projected 1.6 million new diagnoses per year and almost 600,000 deaths. Our understanding of the molecular pathways causing tumor initiation, progression, and metastasis has expanded tremendously in the last 35 years, and drugs specifically designed to inhibit proteins that control these pathways have achieved clinical success. The broad goal of my research encompasses efforts to discover small-molecule targeted inhibitors for three highly validated proteins for which no specific inhibitor had yet been discovered: K-Ras, Pak-1, and Mcl-1. K-Ras is mutated in 30% of human cancers and promotes cell growth, survival, and motility, but is especially challenging to chemically modulate. I discovered compounds that bound to the active, GTP-bound form of K-Ras, which have formed the starting point for an active drug discovery program. Pak-1 likewise regulates a wide variety of pathways implicated in cancer progression, particularly regarding motility and metastasis. To discover a potent Pak-1 inhibitor with selectivity over other Pak family kinases, I conducted first- and second-site fragment-based NMR screens, developed robust in vitro activity assays to measure compound affinities to guide chemical optimization, and measured the effects of in-house synthesized compounds in cells. Mcl-1 is an anti-apoptotic Bcl-2 family member that is frequently upregulated in many cancer types, and prevents apoptosis by binding and sequestering pro-apoptotic Bcl-2 family members. I enabled the understanding of inhibitor structure-activity relationships through the development of highly sensitive biochemical assays, developed assays to determine the on-mechanism actions of these compounds in cells, and defined and predicted the molecular mechanisms of Mcl-1 sensitivity in triple-negative breast cancer and other cancer types. In conclusion, my research has contributed to expanding the pharmacopeia of inhibitors against highly validated oncogenes for the treatment of cancer.