# HTS for TGF-beta receptor assembly inhibitors with anti-tumor and anti-fibrosis activities

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $509,271

## Abstract

The TGF-β isoforms, TGF-β1, -β2, and –β3, are well-known to promote the progression of several different
soft tissue cancers, such as those of the breast, brain, prostate, liver, and lung, as well as promote the
accumulation of extracellular matrix (ECM) that leads to the progression of fibrotic disorders, such as
idiopathic pulmonary fibrosis, cardiac fibrosis, and renal fibrosis. The therapeutic benefit of antagonizing TGF-
βs using small molecule receptor kinase inhibitors (SMRKIs), neutralizing antibodies (NABs), and other
approaches has been amply demonstrated in animals, yet no inhibitors have been approved for treatment of
cancer or fibrosis in humans. The SMRKIs have poor specificity/selectivity and have failed in clinical trials.
Biologics, such as TGF-β pan-isoform NABs, are highly specific and safe, but penetrate poorly into dense
tissues such as tumors and may be unable to effectively bind and neutralize TGF-βs, which are stored in the
extracellular matrix (ECM) as a latent protein bound to their pro-domain, and indirectly, to other ECM proteins
such as LTBP and GARP. The objective of this proposal is to leverage the high specificity of the TGF-βs for
their type II receptor, TβRII, as well as our understanding of the underlying structural basis for this specificity,
to discover and develop a novel class of small molecule assembly inhibitors (SMAIs) that bind either to the
fingertip region of TGF-β or to the corresponding interacting surface of TβRII to block TGF-β:TβRII binding
and the subsequent recruitment of TbRI and signaling. The hypothesis of our proposed research is that SMAIs
that bind in this manner should effectively target the TGF-β pathway in a highly specific manner. This, together
with increased accessibility of an extracellular target for the SMAIs, rather than an intracellular target for the
SMRKIs, should increase the effectiveness of the SMAIs. To discover and develop this promising new class
of small molecule TGF-β inhibitors, we will employ unique protein reagents, developed over many years in
one of the PI’s laboratory, that will enable the reliable identification of inhibitors using a highly sensitive TR-
FRET high throughput screening (HTS) assay that we have developed, optimized, and validated. To enable
the reliable identification of bona fide inhibitors, we will employ two counter screens, a TR-FRET interference
and an orthogonal assay format. We will utilize a panel of cell-based assays to assess pathway selectivity,
potency, and interference with TGF-β stimulated activities, such as EMT and deposition of ECM, that are
known to drive disease progression. To enable future optimization of a lead compound, we will identify the
target protein and determine the structure of the inhibitor bound to the target protein using X-ray
crystallography or NMR and develop an initial SAR based on evaluation of available analogs in biophysical
and functional assays.

## Key facts

- **NIH application ID:** 9974495
- **Project number:** 5R01CA233622-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ANDREW P HINCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,271
- **Award type:** 5
- **Project period:** 2019-07-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974495

## Citation

> US National Institutes of Health, RePORTER application 9974495, HTS for TGF-beta receptor assembly inhibitors with anti-tumor and anti-fibrosis activities (5R01CA233622-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974495. Licensed CC0.

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