A Phase 1, Open-Label, Randomized, Crossover Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single Ascending Doses of APL-1501 ER Capsules Compared to APL-1202 IR Tablets in Healthy Volunteers

The primary objective of the study is to assess safety and tolerability following administration of single doses of APL-1202 (immediate release) IR tablets and APL-1501 extended release (ER) capsules in healthy participants.

Start Date26 Jun 2024

Sponsor / Collaborator

Syneos Health, Inc.

[+1]

NCT06034015 / Not yet recruitingPhase 1

A Phase 1, Two-Part, Open-Label Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of Single Ascending Doses of APL-1501 Extended Release (ER) Capsules Compared to APL-1202 Immediate Release (IR) Tablets in Healthy Volunteers (Part A) and Multiple Ascending Doses of APL-1501 ER Capsules Compared to APL-1202 IR Tablets in Healthy Volunteers (Part B)

This is an integrated Phase 1, single centre, 2-part, open-label, dose-escalation study conducted in healthy volunteers to assess the safety, tolerability, and PK of APL-1501 ER capsules in comparison to APL-1202 IR tablets.

Start Date09 Sep 2023

Sponsor / Collaborator

Asieris Pharmaceuticals Co., Ltd.

100 Clinical Results associated with METAP1 x METAP2

100 Translational Medicine associated with METAP1 x METAP2

0 Patents (Medical) associated with METAP1 x METAP2

Literatures (Medical) associated with METAP1 x METAP2

01 Sep 2024·Journal of Eukaryotic Microbiology

Methionine aminopeptidases: Potential therapeutic target for microsporidia and other microbes

Review

Author: Das, Sasmita ; Weiss, Louis M. ; Saito, Mariko ; Shukla, Srushti ; Das, Bhaskar C. ; Shareef, Mohammed Adil ; Chokkalingam, Parthiban

AbstractMethionine aminopeptidases (MetAPs) have emerged as a target for medicinal chemists in the quest for novel therapeutic agents for treating cancer, obesity, and other disorders. Methionine aminopeptidase is a metalloenzyme with two structurally distinct forms in humans, MetAP‐1 and MetAP‐2. The MetAP2 inhibitor fumagillin, which was used as an amebicide in the 1950s, has been used for the successful treatment of microsporidiosis in humans; however, it is no longer commercially available. Despite significant efforts and investments by many pharmaceutical companies, no new MetAP inhibitors have been approved for the clinic. Several lead compounds have been designed and synthesized by researchers as potential inhibitors of MetAP and evaluated for their potential activity in a wide range of diseases. MetAP inhibitors such as fumagillin, TNP‐470, beloranib, and reversible inhibitors and their analogs guide new prospects for MetAP inhibitor development in the ongoing quest for new pharmacological indications. This perspective provides insights into recent advances related to MetAP, as a potential therapeutic target in drug discovery, bioactive small molecule MetAP2 inhibitors, and data on the role of MetAP‐2 as a therapeutic target for microsporidiosis.

01 Feb 2024·Molecular Cancer Therapeutics

Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models

Article

Author: Hahn, Diane ; Blume, Beatrix ; Czauderna, Frank ; Tong, Amy H Y ; Moffat, Jason ; Bogatyrova, Olga ; Wienke, Dirk ; Chan, Katherine ; Jabs, Julia ; Leuthner, Birgitta ; Kellner, Roland ; Blaukat, Andree ; Ortiz Ruiz, Maria J ; Jaehrling, Frank ; Heinrich, Timo ; Keil, Marina ; Friese-Hamim, Manja ; Zenke, Frank T ; Rohdich, Felix

AbstractN-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score.

01 Sep 2023·Journal of Cellular Physiology

The aminopeptidase LAP3 suppression accelerates myogenic differentiation via the AKT‐TFE3 pathway in C2C12 myoblasts

Article

Author: Nagatomi, Ryoichi ; Takada, Hiroaki ; Murayama, Kazutaka ; Kano, Yutaka ; Naoki, Suzuki ; Tabuchi, Ayaka ; Kitajima, Yasuo ; Osana, Shion

AbstractSkeletal muscle maintenance depends largely on muscle stem cells (satellite cells) that supply myoblasts required for muscle regeneration and growth. The ubiquitin–proteasome system is the major intracellular protein degradation pathway. We previously reported that proteasome dysfunction in skeletal muscle significantly impairs muscle growth and development. Furthermore, the inhibition of aminopeptidase, a proteolytic enzyme that removes amino acids from the termini of peptides derived from proteasomal proteolysis, impairs the proliferation and differentiation ability of C2C12 myoblasts. However, no evidence has been reported on the role of aminopeptidases with different substrate specificities on myogenesis. In this study, therefore, we investigated whether the knockdown of aminopeptidases in differentiating C2C12 myoblasts affects myogenesis. The knockdown of the X‐prolyl aminopeptidase 1, aspartyl aminopeptidase, leucyl‐cystinyl aminopeptidase, methionyl aminopeptidase 1, methionyl aminopeptidase 2, puromycine‐sensitive aminopeptidase, and arginyl aminopeptidase like 1 gene in C2C12 myoblasts resulted in defective myogenic differentiation. Surprisingly, the knockdown of leucine aminopeptidase 3 (LAP3) in C2C12 myoblasts promoted myogenic differentiation. We also found that suppression of LAP3 expression in C2C12 myoblasts resulted in the inhibition of proteasomal proteolysis, decreased intracellular branched‐chain amino acid levels, and enhanced mTORC2‐mediated AKT phosphorylation (S473). Furthermore, phosphorylated AKT induced the translocation of TFE3 from the nucleus to the cytoplasm, promoting myogenic differentiation through increased expression of myogenin. Overall, our study highlights the association of aminopeptidases with myogenic differentiation.

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