Paulex Bio

Our Approach

Today, we stand on the threshold of what could be a transformative breakthrough for type 1 and type 2 diabetes: to stimulate human beta cell proliferation, previously thought to be nearly impossible.  

By stimulating the regeneration of human beta cells through an oral medicine, we’re aiming to restore natural insulin production, addressing the root cause of the disease and potentially offering insulin independence to people across type 1 and type 2 diabetes.

Root Cause of Diabetes

The importance of beta cells

  • Pancreatic beta cells produce insulin and are essential for regulating the amount of glucose in the bloodstream.
  • Beta cells produce insulin in response to food consumption, and insulin allows glucose to move from the blood to all cells in your body to be either stored or consumed as a source of energy.

Addressing the root cause of diabetes

Insufficient beta cell mass – a key driver of both type 1 and type 2 diabetes – leads to inadequate insulin production and hyperglycemia.

The Paulex Bio Solution

Unlocking Beta Cell Regeneration through DYRK1A Inhibitors​

By creating an oral medication to stimulate the regeneration of beta cells through DYRK1 inhibition, we’re aiming to unlock the pancreas to regenerate its population of insulin-producing cells. DYRK1A inhibition could bring beta cells to their optimal regenerative potential.

Unlocking Beta Cell Regeneration

Taking the brakes off beta cell proliferation​

PAL-119 is a selective oral DYRK1A inhibitor designed to remove a key biological “brake” on beta cell growth—enabling the pancreas to regenerate insulin-producing beta cells and increase endogenous insulin production.

  • Early life: Beta cells naturally divide and expand to establish healthy beta cell mass.​
  • With aging: This regenerative capacity declines—beginning as early as puberty—severely limiting the pancreas’s ability to replace lost beta cells.
  • In diabetes: Both type 1 and type 2 diabetes are characterized by a profound loss of functional beta cells.
  • Mechanistic insight: DYRK1A acts as a molecular brake on human beta cell proliferation. Inhibiting DYRK1A re-activates dormant regenerative pathways.
  • Preclinical evidence: Multiple models show that DYRK1A inhibition robustly increases human beta cell proliferation.
  • Functional outcome: Human beta cells transplanted into diabetic mice and treated with a DYRK1A inhibitor demonstrate improved blood glucose control versus controls.
PAL 119 Treatement
Beta Cell Proliferation
beta-cell-proliferation-over-time
DYRK1 Inhibitor

DYRK1A as a central regulator of beta cell proliferation & function​

What is DYRK1A?​

  • DYRK1A (dual-specificity tyrosine-phosphorylation-regulated kinase 1A) is a central regulator of human beta cells.
  • Its activity suppresses not only beta cell proliferation, but also limits programs involved in beta cell maturation and functional identity.

Mechanistic basis of beta cell suppression (Role of DYRK1A)

  • DYRK1A phosphorylates and functionally removes the transcription factor, NFAT, from the nucleus of the cell.​
  • Loss of nuclear NFAT reduces expression of genes required for:
    • Beta cell cell-cycle entry and expansion
    • Beta cell differentiation and maintenance of beta cell identity​
    • Insulin synthesis and glucose-responsive insulin secretion​
  • This mechanism contributes to age-related loss of beta cell regenerative capacity and progressive beta cell dysfunction in diabetes.​

Proposed mechanism of action of PAL-119​

  • PAL-119 selectively inhibits DYRK1A, restoring NFAT nuclear localization and transcriptional activity.
  • Reactivation of NFAT-dependent programs supports:
    • Regeneration of beta cell mass through controlled proliferation
    • Reinforcement of beta cell differentiation and identity
    • Improved insulin production and secretory capacity
  • Together, these effects are expected to promote healthier, more functional beta cells
What is PAL-119

Experts Explain the Science

Renowned endocrinologists and diabetes experts share their insights on diabetes, Paulex Bio, and its mission to bring an end to diabetes.

On the Path to a Functional Cure for Diabetes

Helping the Human Body Bring an End to Diabetes

A Transformative Approach in Diabetes Treatment.

On the Path Forward

Stay updated with our latest developments, research breakthroughs, and company milestones.

View all latest News & Media

Publications

2015

Wang P, Alvarez-Perez JC, Felsenfeld DP, et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015;21(4):383-388. doi:10.1038/nm.3820 https://pmc.ncbi.nlm.nih.gov/articles/PMC4690535/

2018

Kumar K, Wang P, Sanchez R, Swartz EA, Stewart AF, DeVita RJ. Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation. J Med Chem. 2018;61(17):7687-7699. doi:10.1021/acs.jmedchem.8b00658 https://pmc.ncbi.nlm.nih.gov/articles/PMC6350255/

2019

Wang P, Karakose E, Liu H, et al. Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells. Cell Metab. 2019;29(3):638-652.e5. doi:10.1016/j.cmet.2018.12.005 https://pmc.ncbi.nlm.nih.gov/articles/PMC6402958/

2020

Kumar K, Wang P, A Swartz E, et al. Structure-Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation. Molecules. 2020;25(8):1983. doi:10.3390/molecules25081983 https://pmc.ncbi.nlm.nih.gov/articles/PMC7221803/

Kumar K, Wang P, Wilson J, et al. Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor. J Med Chem. 2020;63(6):2986-3003. doi:10.1021/acs.jmedchem.9b01379 https://pmc.ncbi.nlm.nih.gov/articles/PMC7388697/

Ackeifi C, Wang P, Karakose E, et al. GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration. Sci Transl Med. 2020;12(530):eaaw9996. doi:10.1126/scitranslmed.aaw9996 https://pmc.ncbi.nlm.nih.gov/articles/PMC9945936/

Ackeifi C, Swartz E, Kumar K, et al. Pharmacologic and genetic approaches define human pancreatic β cell mitogenic targets of DYRK1A inhibitors. JCI Insight. 2020;5(1):e132594. doi:10.1172/jci.insight.132594 https://pmc.ncbi.nlm.nih.gov/articles/PMC7030849/

2021

Wang P, Karakose E, Choleva L, et al. Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges. Front Endocrinol (Lausanne). 2021;12:671946. doi:10.3389/fendo.2021.671946 https://pmc.ncbi.nlm.nih.gov/articles/PMC8322843/

2024

Ables JL, Israel L, Wood O, et al. A Phase 1 single ascending dose study of pure oral harmine in healthy volunteers. J Psychopharmacol. 2024;38(10):911-923. doi:10.1177/02698811241273772 https://pmc.ncbi.nlm.nih.gov/articles/PMC11549898/

Karakose E, Wang X, Wang P, et al. Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors. Cell Rep Med. 2024;5(12):101832. doi:10.1016/j.xcrm.2024.101832 https://pmc.ncbi.nlm.nih.gov/articles/PMC11722108/

Rosselot C, Li Y, Wang P, et al. Harmine and exendin-4 combination therapy safely expands human β cell mass in vivo in a mouse xenograft system. Sci Transl Med. 2024;16(755):eadg3456. doi:10.1126/scitranslmed.adg3456 https://pmc.ncbi.nlm.nih.gov/articles/PMC12051162/

Wang P, Wood O, Choleva L, et al. Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells. Preprint. bioRxiv. 2024. doi:10.1101/2024.05.17.594179 https://pmc.ncbi.nlm.nih.gov/articles/PMC11118480/