Direct Inhibitors of Ras-Effector Protein Interactions

Abstract

Activating Ras mutations are associated with ~30% of all human cancers, which often respond poorly to standard therapies. The four Ras isoforms are therefore highly attractive targets for anticancer drug discovery. However, Ras proteins function through protein-protein interactions and their surfaces lack any major pockets for small molecules to bind; as a result they have been declared "undruggable" for the past 30 years. Several breakthroughs during the past few years may finally remove Ras from the list of undruggable proteins. This mini-review discusses the current approaches to developing inhibitors especially cyclic peptides that physically block the interaction between Ras and its downstream effector proteins, which is potentially the most effective approach for treating Ras mutant cancers.

Targeting the α4-α5 interface of RAS results in multiple levels of inhibition

“…23 Furthermore, superresolution microscopy supports the premise that RAS proteins form dimers at the plasma membrane. 17 However, these dimers were independent of the activation state of RAS and mediated by the hypervariable region. 17 Our analysis of H-RAS crystal structures reveals the presence of a unique a4-a5 dimeric structure in "active" H-RAS that is not present in "inactive" state H-RAS structures, suggesting weak propensity of the G-domain to dimerize using the a4-a5 interface.…”

“…13,14 This same hydrophobic pocket has been used to prevent RAF interaction, which led to increased apoptosis in an N-RAS-mutant (Q61K) non-small cell lung cancer line, H1299. 16,17 SOS interaction has also been targeted using a cell permeable peptide based on the RAS-interacting a-helix 1 of SOS that blocks the interaction of K-RAS with SOS1 and further prevents GTP association, resulting in inhibition of K-RAS function. 18 However, none of these antagonists possess sufficient affinity and efficacy to potently block RAS function in a therapeutically relevant setting.…”

Direct inhibition of RAS: Quest for the Holy Grail?

“…4 & 5B). 64 Interestingly, these compounds bound the same hydrophobic region as DCAI 19 and Cyclorasin 9A5, 65 but made somewhat different contacts with RAS (Fig. 5B).…”

Identification of a New Potent Inhibitor Targeting KRAS in Non-small Cell Lung Cancer Cells

“…To date, there are mainly three strategies for the discovery of potent KRAS inhibitors: (1) to inhibit KRAS membrane targeting ( Laheru et al, 2012 ; Prakash and Gorfe, 2013 ; Chavan et al, 2015 ; Cox et al, 2015 ); (2) to directly target KRAS ( Wang et al, 2012 ; Cromm et al, 2015 ; Leshchiner et al, 2015 ; Brock et al, 2016 ; Trinh et al, 2016 ); (3) to inhibit interaction between KRAS and its downstream effectors ( Athuluri-Divakar et al, 2016 ; Upadhyaya et al, 2016 ; Keeton et al, 2017 ). However, there are multiple escape pathways by process of post-translation for inhibiting KRAS membrane targeting ( Rowinsky et al, 1999 ; Van Cutsem et al, 2004 ).…”