The PKM2 activator and molecular glue TP-1454 modulates tumor-immune responses by destabilizing T-regulatory cells

Background: Pyruvate kinase is an important enzyme that catalyzes the last step of glycolysis. The M2 isoform (PKM2) for balancing respiration and biosynthesis, which can be achieved by switching between highly active tetrameric form less dimeric through allosteric metabolite binding. In addition to its role in metabolic regulation, PKM2 translocate nucleus, altering transcription enhance cancer cells’ ability grow evade immune detection. Targeting activation presents opportunity potentially reprogram tumor-immune microenvironment (TME). TP-1454 a potent activator achieving with low nanomolar concentration biochemical assays (AC50 = 10 nM). has acceptable preclinical safety profile currently Phase I clinical trial (NCT04328740). Materials Methods: activity was measured using colorimetric assay. tetramerization Foxp3 protein stability assayed western blots. vivo alone combination checkpoint inhibitors (CPI) tested multiple syngeneic mouse models. Flow cytometry used conduct immunophenotyping cells TME test regulatory T cell (Treg) polarization. Treg proliferation assessed Cell Trace Violet Assay. Mass spectrometry conducted identify changes levels. post-translational modifications were Foxp3-Flag expressing HEK293 line. Results: treatment increased vitro showed dose-dependent increase tetramer formation. Oral administration resulted substantial [KK1] [SS2] antitumor as single agent (up 42% tumor growth inhibition compared vehicle) CPI (100% complete response, 58% mean survival alone) various types differential activation. reduced intratumoral CD4+ Foxp3+ levels immunophenotyping. reduction polarization but not proliferation. Human peripheral blood mononuclear (PBMC) treated decrease glucosamine-6-phopsphate (G6P), reported stabilize via O-linked β-N-acetylglucosamine (O-GlcNac) modification. O-GlcNac-Foxp3 faster degradation. Conclusions: These findings suggest novel mechanism regulate models should investigated further trials. Conflict interest: Corporate-sponsored Research: Employment