Method of increasing proliferation of pancreatic beta cells, treatment method, and composition
Inventors
Stewart, Andrew F. • ACKEIFI, Courtney • Wang, Peng • DeVita, Robert J.
Assignees
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Publication Number
US-12630803-B2
Publication Date
2026-05-19
Expiration Date
Abstract
Disclosed herein are methods of increasing cell proliferation in a population of pancreatic beta cells. Also disclosed are methods of treating a subject for a condition associated with insufficient insulin secretion. Also disclosed is a composition comprising a DYRK1A inhibitor and a GLP1R agonist. The disclosure further describes a method of regenerating pancreatic beta cells in a transplant patient.
Core Innovation
The disclosure describes small molecules containing benzimidazole/acetyl or bromoacetyl carboxamide motifs and thiadiazinone/thiadiazinamine motifs, including multiple N-substituted-5-(benzo[d]imidazol-2(3H)-one)-6H-1,3,4-thiadiazin-2-amine derivatives with varied aryl/heteroaryl or alkyl substituents. The document also characterizes thiadiazine kinase inhibitors as chemical structures and names for DYRK1A inhibitor chemotypes, and presents these derivatives as candidate DYRK1A inhibitor chemotypes for combination treatment.
The disclosure describes combinations that pair DYRK1A inhibitors, including harmine and other listed DYRK1A inhibitor examples, with glucagon-like peptide-1 receptor (GLP1R) agonists. The stated problem is treatment of a condition associated with insufficient insulin secretion, with the goal of increasing glycemic control, and the independent claim coverage is directed to dual administration of a DYRK1A inhibitor and a GLP1R agonist under conditions effective to increase glycemic control.
The disclosure focuses on synergistic induction of human pancreatic beta-cell proliferation and beta-cell mass when a DYRK1A inhibitor is combined with a GLP1R agonist. It states that DYRK1A inhibition together with increased intracellular cAMP/PKA/EPAC signaling increases human beta-cell replication rates beyond DYRK1A inhibitors alone, increases actual pancreatic beta-cell numbers without dedifferentiation, and maintains differentiation markers while preserving insulin secretion, with effects extended to T2D islets.
Claims Coverage
The consolidated claim coverage centers on one independent method claim directed to treating a human subject with a condition associated with insufficient insulin secretion by administering a DYRK1A inhibitor and a GLP1R agonist under conditions effective to increase glycemic control. Dependent claims specify selected DYRK1A inhibitors and GLP1R agonists, harmine together with GLP1 (7-36), routes of administration, and a quantitative beta-cell proliferation range.
Dual administration of a DYRK1A inhibitor and a GLP1R agonist to increase glycemic control
A method of treating a human subject with a condition associated with insufficient insulin secretion by administering a dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitor and a glucagon-like peptide-1 receptor (GLP1R) agonist under conditions effective to cause an increase in glycemic control.
Selected DYRK1A inhibitor candidates
The DYRK1A inhibitor is selected from harmine, INDY, leucettine-41, 5-iodotubercidin (5-IT), GNF4877, CC-401, thiadiazine kinase inhibitors, or combinations thereof.
Selected GLP1R agonist candidates
The GLP1R agonist is selected from GLP1 analogs, extendin-4, liraglutide, lixisenatide, or combinations thereof.
Harmine together with GLP1 (7-36)
The method includes administering harmine together with GLP1 (7-36).
Routes of administration
Administering the treatment is performed by one of several routes including nasal, oral, transdermal, parenteral, subcutaneous, intravenous, intramuscular, or intraperitoneal delivery.
Quantitative beta-cell proliferation range
The method further includes administering an agent that increases the number of proliferating pancreatic beta cells in the subject by about 4–6% per day.
Overall, the claims are directed to treatment of insufficient insulin secretion by dual administration of a DYRK1A inhibitor and a GLP1R agonist to increase glycemic control, with dependent coverage for selected inhibitor and agonist candidates, harmine plus GLP1 (7-36), specified routes, and a quantified beta-cell proliferation increase.
Stated Advantages
Increase in glycemic control in a subject with a condition associated with insufficient insulin secretion.
Increase in human beta-cell replication rates beyond DYRK1A inhibitors alone.
Increase in actual pancreatic beta-cell numbers without dedifferentiation.
Maintains differentiation markers while preserving insulin secretion.
Increase in the number of proliferating pancreatic beta cells by about 4–6% per day.
Documented Applications
Treatment of a human subject for a condition associated with insufficient insulin secretion.
Diabetes-related regeneration of pancreatic beta cells using a synergistic combination therapy including a DYRK1A inhibitor and a GLP1R agonist.
Type 2 diabetes donor islet use cases described in the disclosure for the treatment effects.
Alternative synergy using GLP1R-activating DPP4 inhibitors is described.
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