# Disease-modifying drugs for T2D through targeting the Unfolded Protein Response

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $683,334

## Abstract

Project Summary/Abstract
Type 2 diabetes (T2D) is a chronic degenerative cell disease characterized by hyperglycemia due to
progressive progressive loss of overworked pancreatic islet beta cells. Recent work from our laboratories has
shown that hyperactivation of the unfolded protein response (UPR) to ER stress in beta cells due to upstream
may be a critical early event in the development of T2D. We have developed and are refining novel small
molecule pharmacological reagents that allow us to manipulate critical components of the UPR—called KIRAs
that maintain desirable (adaptive) outputs of the UPR while quelling undesirable (maladaptive) outputs
including insulin resistance in peripheral tissues, consequently leading to apoptosis and diabetes. We show
that first generation versions of KIRAs we developed against a kinase/RNase target called IRE1α can
efficaciously prevent and even reverse diabetes in leptin deficient ob/ob mice. Here, we plan a medicinal
chemistry campaign using several strategies to optimize KIRAs on three scaffolds towards the clinic. In this
collaborative grant we will capitalize on the complementary expertise of the investigators to optimize these
KIRA lead molecules for potency, selectivity, drug-likeness (including oral bioavailability) and conduct critical
proof-of-concept studies using reductionist chemical genetic systems, ob/ob and HFD-fed mice, and human
islets, and perform key IND-enabling steps needed to advance these candidates further into the clinic for
eventually treating human patients with T2D.

## Key facts

- **NIH application ID:** 10905900
- **Project number:** 1R01DK137545-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Dustin J Maly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,334
- **Award type:** 1
- **Project period:** 2024-04-17 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905900

## Citation

> US National Institutes of Health, RePORTER application 10905900, Disease-modifying drugs for T2D through targeting the Unfolded Protein Response (1R01DK137545-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10905900. Licensed CC0.

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