# Mitigation of Exaggerated Smooth Muscle Force with Inhibitors of Integrin Alpha2Beta1

> **NIH NIH R33** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $565,171

## Abstract

PROJECT SUMMARY/ABSTRACT
 This is a new submission for an R61/R33 award for Dr. Aparna Sundaram (Assistant Professor,
Department of Medicine) and Dr. Hyunil Jo (Assistant Professor, Department of Pharmaceutical Chemistry) at
the University of California, San Francisco (UCSF). The long-term objectives of this proposal are to develop
novel small molecule inhibitors of integrin α2β1 to disrupt force transmission in airway smooth muscle in
chronic airways diseases such as asthma.
 Recent data published by Drs. Sundaram and Jo have shown that targeting proteins involved in smooth
muscle tethering can impair force transmission in asthma models. Inhibition of these proteins result in
protection against the exaggerated contraction induced by asthmagenic cytokines such as IL-13 ex vivo, or
airway hyperresponsiveness in allergic airways disease models in vivo. Drs. Sundaram and Jo have shown
that these protective effects occur independently of changes in intracellular actin-myosin crossbridging by
directly modulating the tethering of smooth muscle to the surrounding matrix, suggesting that they can be
combined with currently available bronchodilators acting on smooth muscle to further enhance relaxation.
 In this proposal Drs. Sundaram and Jo present preliminary data underscoring the importance of the
smooth muscle tethering protein, integrin α2β1; ligation of this integrin results in protection against IL-13
enhanced contraction ex vivo and airway hyperresponsiveness in vivo. They have further shown proof of
principle with the parent compound c15, and have made significant improvements in potency with A2-85, and
even further optimization for oral delivery with compounds identified in this proposal. The R61 phase of this
proposal seeks to synthesize and screen potent and specific small molecule inhibitors of integrin α2β1 with a
structure-based-drug-design approach (Aim 1). Compounds will be further narrowed with in vitro optimization
and ex vivo validation (Aim 2). Finally, hit compounds will be selected based on
pharmacokinetic/pharmacodynamic studies to optimize oral delivery and in vivo testing in relevant disease
models (Aim 3). The R33 phase of this proposal will further focus on lead series optimization. This proposal
combines the efforts of two scientists with expertise in smooth muscle biology and de novo drug design who
have already successfully collaborated together on the design and development of novel integrin inhibitors,
along with a seasoned team of collaborators and consultants with experience in pre-clinical drug development.
Accordingly, the R61 phase of this proposal aims to provide a lead series and the subsequent R33 phase will
further focus on selection of a developmental candidate for therapeutic use in poorly controlled asthma.

## Key facts

- **NIH application ID:** 10972754
- **Project number:** 4R33HL163725-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Hyunil Jo
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,171
- **Award type:** 4N
- **Project period:** 2022-05-26 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10972754

## Citation

> US National Institutes of Health, RePORTER application 10972754, Mitigation of Exaggerated Smooth Muscle Force with Inhibitors of Integrin Alpha2Beta1 (4R33HL163725-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10972754. Licensed CC0.

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