Delving into the Latest Updates on BI-4924 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PHGDH

Mechanism

PHGDH inhibitors(phosphoglycerate dehydrogenase inhibitors)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Boehringer Ingelheim Corp.

Active Organization

Boehringer Ingelheim Austria GmbH

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC21H20Cl2N2O6S

InChIKeyCJEJFFCPVBZSIE-OAHLLOKOSA-N

CAS Registry2244452-09-1

Author: Harrer, Christoph ; Gerstberger, Thomas ; Sharps, Bernadette ; Ettmayer, Peter ; Lv, Xiaobing ; Schnitzer, Renate ; Peric-Simov, Biljana ; Rumpel, Klaus ; Zoephel, Andreas ; Du, Alicia ; Treu, Matthias ; Li, Dongyang ; Quant, Jens ; Weinstabl, Harald ; Fett, Thomas N. ; McConnell, Darryl B. ; Zhang, Xuechun ; Sommergruber, Wolfgang ; Ciftci, Tuncay ; Li, Yali ; Arnhof, Heribert ; Scholz, Guido ; Garavel, Géraldine ; Hofbauer, Karin S. ; Mitzner, Sophie ; Wolkerstorfer, Bernhard ; Bader, Gerd ; Burkard, Michelle ; Dahmann, Georg ; Mayer, Moriz ; Martinelli, Paola ; Savarese, Fabio ; Zahn, Stephan K. ; Pearson, Mark ; Mischerikow, Nikolai ; Rinnenthal, Joerg ; Bruchhaus, Jens ; Haering, Daniela ; Schrenk, Andreas ; Scherbantin, Yvonne ; Kousek, Roland ; Kessler, Dirk

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD⁺)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD⁺.

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