Targeting guanine nucleotide exchange factors for novel cancer drug discovery

ABSTRACT

Introduction

Guanine nucleotide exchange factors (GEFs) regulate the activation of small GTPases (G proteins) of the Ras superfamily proteins controlling cellular functions. Ras superfamily proteins act as ‘molecular switches’ that are turned ‘ON’ by guanine exchange. There are five major groups of Ras family GTPases: Ras, Ran, Rho, Rab and Arf, with a variety of different GEFs regulating their GTP loading. GEFs have been implicated in various diseases including cancer. This makes GEFs attractive targets to modulate signaling networks controlled by small GTPases.

Areas covered

In this review, the roles and mechanisms of GEFs in malignancy are outlined. The mechanism of guanine exchange activity by GEFs on a small GTPase is illustrated. Then, some examples of GEFs that are significant in cancer are presented with a discussion on recent progress in therapeutic targeting efforts using a variety of approaches.

Expert opinion

Recently, GEFs have emerged as potential therapeutic targets for novel cancer drug development. Targeting small GTPases is challenging; thus, targeting their activation by GEFs is a promising strategy. Most GEF-targeted drugs are still in preclinical development. A deeper biological understanding of the underlying mechanisms of GEF activity and utilizing advanced technology are necessary to enhance drug discovery for GEFs in cancer.

KEYWORDS:

• Drug discovery
• guanine nucleotide exchange factors
• small GTPases
• cancer
• Ras proteins

Article highlights

• GEFs regulate Ras superfamily GTPases and control signaling pathways by diverse mechanisms.

• GEFs catalyze guanine nucleotide exchange on G proteins via a general mechanism, dissociating GDP to enable GTP loading.

• Aberrant GEF activity has been implicated in carcinogenesis.

• The RAS GEF known as SOS1 has been widely studied as a target in RAS-driven cancers.

• Rho, Arf, and Ran GEFs are also potential drug targets in need of further characterization.

• GEFs represent attractive novel therapeutic targets for cancer drug development.

Declaration of Interest

The authors thank the SKY Foundation Inc. for their generous support. SF Bannoura acknowledges the generous support from the DeRoy Testamentary Foundation. AS Azmi has received funding from Blackstone Therapeutic, Purple Biotech and FanWave Therapeutics, unrelated to this work. BC Pasche also declares that he owns stock in Therabionic Inc and TheraBionic GmbH that is unrelated to this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Work in the lab of AS Azmi is supported by National Institutes of Health/National Cancer Institute grants [R37CA215427-07] and [R01 CA240607-04].