MK0339 / Merck (MSD) - LARVOL DELTA

Deciphering Genotype-Phenotype Correlations and the Mechanism of the Action of Neutrophil Elastase Inhibitors during ELANE Associated Neutropenia Utilizing Molecular Modeling Software (ASH 2024) - "Molecular docking analysis of 4 small molecule, cell permeable NE inhibitors (MK0339, sivelestat, GW311616, BAY-678) and inactive control, BAY-677, revealed an alternative binding site for MK0339 inhibitor compared to all others. Conclusions : Molecular modeling software analysis of the effect of high- and low-risk mutations on NE protein structure may be key for understanding genotype-phenotype correlations for ELANE associated neutropenia. The current results of molecular docking and inhibitor-protein complex analysis via molecular modeling software correlates with our previous studies and suggests that MK0339 forms a much more stable complex with w-type and mutant NE protein compared to the other inhibitors tested, a valuable insight for developing a therapeutic agent for ELANE associated neutropenia."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • ELANE

Evaluation of Neutrophil Elastase Inhibitors as Potential Therapies for ELANE Associated Neutropenia. (PubMed, J Cell Immunol) - "In contrast, other NE inhibitors, i.e., sivelestat, BAY-678, and GW311616 and the DPP1 inhibitor, brensocatib, showed no effect on neutrophil differentiation. Molecular docking studies showed that MK0339 binds to an alternative site on the NE protein compared to other inhibitors with greater inhibitor-NE protein stability, suggesting a unique mechanism of action and supporting further investigation of MK0339 as a therapy for ELANE associated neutropenia."

Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Musculoskeletal Pain • Myelodysplastic Syndrome • Neutropenia • Oncology • Pain • Transplantation • CD14 • CD34 • CEACAM8 • ELANE • ITGAM

The Effect of Neutrophil Elastase Inhibitors on in-Vitro Myeloid Differentiation of CD34+ Cells of Patients with ELANE Associated Neutropenia (ASH 2022) - "We used Merck developed MK-0339, Sivelestat (MedChemExpress) and GW311616 (MedChemExpress) cell permeable NE inhibitors. The results with this initial patient, together with our previous studies using HL60 cells, indicate that some, but not all, selective NE inhibitors can correct the cellular abnormalities in ELANE associated neutropenia. We are investigating the effectiveness of this potential therapeutic approach across a diversity of mutations and other cell permeable NE inhibitors. Current evidence suggests that a clinical trial of MK-0339 is justified if there is supportive data on the safety of administration of this compound."

Preclinical • Bone Marrow Transplantation • Hematological Disorders • Neutropenia • Transplantation • CD14 • CD34 • CEACAM8 • ELANE • ITGAM

Comparison of Gene Editing versus a Neutrophil Elastase Inhibitor as Potential Therapies for ELANE Neutropenia. (PubMed, J Cell Immunol) - "ATRA induced differentiation demonstrated comparably impaired myeloid cell development for all three lines with upregulated expression of GRP78/BIP, an abnormality corrected by exposure of these cells to the elastase inhibitor MK-0339...We concluded that both strategies have great potential for the treatment of cyclic and congenital neutropenia. However, an orally absorbed, cell permeable inhibitor of neutrophil elastase, if proven safe and effective in a clinical trial, might be the better alternative to G-CSF or gene editing to treat ELANE neutropenia."

Journal • Hematological Disorders • Hematological Malignancies • Neutropenia • Oncology • ELANE • HSPA5