# Targeting of non-canonical G protein signaling with small molecules

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $357,112

## Abstract

The high importance of signaling via heterotrimeric G proteins in
physiology and disease is reflected by the fact that G protein-coupled receptors (GPCRs), which activate G
proteins, are the target for more that >25% of FDA-approved drugs. Interestingly, recent work by us and others
has led to the identification a novel mechanism of trimeric G protein activation that is mediated by cytoplasmic,
non-receptor proteins instead of membrane-bound GPCRs. Although this mechanism has important
implications in human disease and targeting it is a novel opportunity to develop therapeutic approaches, it
remains completely unexploited form a pharmacological standpoint. Our goal is to carry out proof-of-
concept studies for early stage drug development of first-in-class small molecule inhibitors of a GPCR-
independent mechanism of G protein activation that promotes cancer metastasis. More specifically, our
efforts will be focused on developing and characterizing small molecules that disrupt the protein-protein
interaction (PPI) formed between the G protein Gαi and its non-receptor activator GIV (aka Girdin). Many
independent studies have demonstrated that GIV is upregulated in metastatic carcinomas. Upon GIV
overexpression, the GIV-Gαi PPI enhances signaling responses that lead to increased tumor cell migration and
invasion. Thus, inhibition of the GIV-Gαi PPI is a vulnerability of metastatic tumor cells that might provide a
therapeutic window to treat aggressive metastatic cancers. This is of paramount significance because
metastasis is the cause of >90% of cancer related deaths and there are very limited therapeutic options for it.
PRELIMINARY DATA AND EXPERIMENTAL PLAN: In recently published work, we have characterized the
structure of the GIV-Gαi interface and demonstrated that it can be disrupted by small molecules. We have
subsequently performed a screen of 200,000 compounds. We confirmed hits identified in the primary screen
with an orthogonal biochemical assay, filtered out compounds with chemical liabilities and validated them
analytically after re-purchase/re-synthesis. After evaluation in biological assays, we have identified small
molecules based on four unrelated, synthetically tractable scaffolds that disrupt the GIV-Gαi PPI with IC50's in
the ~0.5-30 µM range and that display the expected biological activity of blocking tumor cell migration without
undesired non-specific toxicity. We hypothesize that these compounds selectively disrupt the GIV-Gαi PPI to
block the signaling and cell behavioral processes by which this PPI drives tumor invasiveness, and that upon
optimization, these compounds will have therapeutic effects in pre-clinical models of metastasis. In Aim 1 we
will comprehensively characterize the mode of action of the newly identified inhibitors using biochemical,
biophysical and cell-based approaches, while in Aim 2 we will optimize the most promising of our compounds
to increase its potency and druglike properties to achieve therapeu...

## Key facts

- **NIH application ID:** 9948700
- **Project number:** 5R01GM130120-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Mikel Garcia-Marcos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,112
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948700

## Citation

> US National Institutes of Health, RePORTER application 9948700, Targeting of non-canonical G protein signaling with small molecules (5R01GM130120-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948700. Licensed CC0.

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