# DYRK Inhibitors for Human Beta Cell Expansion

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $717,853

## Abstract

This is a competing renewal for R-01 DK 105015, which ran for four years from 3/01/16 to 2/29/20. The
project focuses on developing drugs that induce human beta cells to regenerate for people with Type 1 and Type 2
diabetes (T1D and T2D), both of which ultimately result from inadequate numbers of normally functioning beta cells.
Small molecule drugs that inhibit the kinase, DYRK1A, such as harmine and others, are very reproducibly able to
induce adult human beta cells to replicate, but at low rates (~2%/day). More recently, we have shown that adding
any small molecule DYRK1A inhibitor to either a TGF-beta superfamily inhibitor (TGFβI’s) or to a GLP1 receptor
agonist (GLP1RA), such as GLP1 or exendin-4, markedly enhances beta cell proliferation to rates averaging 5-
8%/day, and that this translates to marked increases in actual numbers and mass of human beta cells in vivo, when
transplanted into NOD-SCID-gamma (NSG) mice. Thus, during the period of this grant, through the work of
ourselves and others, the field of human beta cell regeneration for T1D and T2D has transitioned from impossible to
clearly possible.
 In this proposed renewal, we seek to learn why some DYRK1A inhibitors - but not others - are able to
enhance human beta cell differentiation and function, while also driving beta cell proliferation. Maintaining beta cell
differentiation will be an essential feature of any beta cell regenerative drug. We expect to identify the underlying
signaling pathway(s) that explain this surprising and very positive effect. We also will explore the efficacy of
DYRK1A inhibitors, in combination with GLP1RA’s, in essential but previously unexplored animal models of T1D
and T2D, strengthening pre-clinical relevance. Finally, using sophisticated medicinal chemistry approaches, we
have identified, synthesized and patented entirely novel and extremely potent human beta cell regenerative
DYRK1A inhibitors. We now need to optimize, using computational predictions and advanced medicinal chemical
syntheses, cleavable linkers designed to attach our next-generation potent and selective human beta cell DYRK1A
inhibitors to potential beta cell-targeting molecules. Thus, the Specific Aims of this application are to:
1. Decipher Mechanisms Underlying the Beneficial Pro-Differentiation Effects of Select DYRK1A Inhibitors.
2. Define in vivo Efficacy of DYRK1A inhibition in Type 1 and Type 2 Diabetes Models.
3. Develop Linkers to Novel Classes of DYRK1A Inhibitors for Targeted Delivery to Beta Cells.
 These goals are both achievable and directly responsive to the goals of aims of the NIDDK. They provide a
realistic basis for generating a new and urgently needed class of therapeutics for T1D and T2D.

## Key facts

- **NIH application ID:** 10427445
- **Project number:** 5R01DK105015-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Robert J DeVita
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $717,853
- **Award type:** 5
- **Project period:** 2016-03-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427445

## Citation

> US National Institutes of Health, RePORTER application 10427445, DYRK Inhibitors for Human Beta Cell Expansion (5R01DK105015-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10427445. Licensed CC0.

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