Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug

0565069 - ÚOCHB 2023 RIV US eng J - Článek v odborném periodiku
Rais, R. - Lemberg, K. M. - Tenora, Lukáš - Arwood, M. L. - Pal, A. - Alt, J. - Wu, Y. - Lam, J. - Aguilar, J. M. H. - Zhao, L. - Peters, D. E. - Tallon, C. - Pandey, R. - Thomas, A. G. - Dash, R. P. - Seiwert, T. - Majer, Pavel - Leone, R. D. - Powell, J. D. - Slusher, B. S.
Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug.
Science Advances. Roč. 8, č. 46 (2022), č. článku eabq5925. ISSN 2375-2548. E-ISSN 2375-2548
Grant CEP: GA MŠMT LTAUSA18166
Institucionální podpora: RVO:61388963
Klíčová slova: 6-diazo-5-oxo-l-norleucine DON * phase II * glutamine metabolism
Obor OECD: Organic chemistry
Impakt faktor: 13.6, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1126/sciadv.abq5925

6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials, however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression, however, DRP-104 had a markedly improved tolerability profile. DRP-104’s effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.
Trvalý link: https://hdl.handle.net/11104/0336617