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Review
. 2022 Mar 24;65(6):4403-4423.
doi: 10.1021/acs.jmedchem.1c01577. Epub 2022 Mar 3.

Boosting the Discovery of Small Molecule Inhibitors of Glucose-6-Phosphate Dehydrogenase for the Treatment of Cancer, Infectious Diseases, and Inflammation

Ana Koperniku  1 , Adriana A Garcia  1 , Daria Mochly-Rosen  1
Affiliations
Review

Boosting the Discovery of Small Molecule Inhibitors of Glucose-6-Phosphate Dehydrogenase for the Treatment of Cancer, Infectious Diseases, and Inflammation

Ana Koperniku et al. J Med Chem. .

Abstract

We present an overview of small molecule glucose-6-phosphate dehydrogenase (G6PD) inhibitors that have potential for use in the treatment of cancer, infectious diseases, and inflammation. Both steroidal and nonsteroidal inhibitors have been identified with steroidal inhibitors lacking target selectivity. The main scaffolds encountered in nonsteroidal inhibitors are quinazolinones and benzothiazinones/benzothiazepinones. Three molecules show promise for development as antiparasitic (25 and 29) and anti-inflammatory (32) agents. Regarding modality of inhibition (MOI), steroidal inhibitors have been shown to be uncompetitive and reversible. Nonsteroidal small molecules have exhibited all types of MOI. Strategies to boost the discovery of small molecule G6PD inhibitors include exploration of structure-activity relationships (SARs) for established inhibitors, employment of high-throughput screening (HTS), and fragment-based drug discovery (FBDD) for the identification of new hits. We discuss the challenges and gaps associated with drug discovery efforts of G6PD inhibitors from in silico, in vitro, and in cellulo to in vivo studies.

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Conflict of interest statement

We declare no competing interests.

Figures

Figure 1.
Figure 1.
The Pentose Phosphate Pathway (PPP); implication in redox homeostasis and cell proliferation.
Figure 2.
Figure 2.
DHEA 1, EA 2, and newer steroidal analogues as inhibitors of hG6PD and TrG6PD.
Figure 3.
Figure 3.
Derivatives of 6 as selective (7a-7b, selective for TrG6PD over hG6PD) and potent (7c, 8a-c) steroidal inhibitors.
Figure 4.
Figure 4.
Thienopyrimidine- and quinazoline-containing compounds of type 9 and 10: potent against recombinant TrG6PD; IC50 values and ranges come from measurements against recombinant TrG6PD.
Figure 5.
Figure 5.
A. Overlay hG6PD (PDB ID: 2BH9) and TrG6PD (PDB ID: 5AQ1), grey for hG6PD and purple for TrG6PD; B. Overlay of the catalytic G6P site hG6PD-TrG6PD; C. Overlay of the structural NADP+ in hG6PD with respective region in TrG6PD lacking the structural NADP+. D. Overlay of the catalytic NADP+ site hG6PD-TrG6PD.
Figure 6.
Figure 6.
Compounds of type 11 and 14 as promiscuous substrates for Michael addition.
Figure 7.
Figure 7.
a. Commercially available 18 (C276–1187) and 19 (D052–0147) shown to inhibit P.falciparum; b. Pyrimidine triazinediones 19, 22, 23 lead to radical intermediates 21 and H2O2 release; c. Strategy of replacing triazine with pyridazine to prevent first reduction step shown in 7b.
Figure 8.
Figure 8.
Generic benzothiazinone ring, essential features for activity, SAR exploration and specific PfGluPho compound 25.
Figure 9.
Figure 9.
Compounds 26–28, in vitro biochemical activity Ki for G6P, and proposed interactions of non-glucosidic compound 25 and glucosidic compounds 26–28 with Asp370.
Figure 10.
Figure 10.
Compounds 25 (ML276) and compound 29 (ML304). 3D alignment performed with Schrödinger 2021–3, Maestro, using largest Bemis-Murcko scaffold. ML276 and ML304 as taken from the original paper.
Figure 11.
Figure 11.
Generic structures of non-steroidal G6PD inhibitors used in infectious diseases, inflammation, and cancer. Main core observed in all cases: quinazolinone. Ligand alignment performed with Schrödinger 2021–3, Maestro, using largest Bemis-Murcko scaffold. M: mixed-type, NC: non-competitive, C: competitive, MOI: modality of inhibition. Biorender.com was used in part for Figure 11.
Figure 12.
Figure 12.
a. Compounds 34a, 34, 35a, 35b showed inhibitory activity against hG6PD and used for blind molecular docking; Codes in parenthesis as taken from the original paper. Ligand alignment performed with Schrödinger 2021–3, Maestro, using largest Bemis-Murcko scaffold for 34a & 34b and sample reference 35a for 35a, 35b & 35; b. Preferred conformation of the nitro compounds 35, 35a & 35b: overlap of the non-bonding lone pair of oxygen with the σ* orbital of sulfur.
Figure 13.
Figure 13.
Top: from estradiol (36) to DES (37) to tamoxifen (38); bottom; perspective for transition of steroidal 1, 2, 6 to non-steroidal analogues.
Figure 14.
Figure 14.
AMG510 39, selective KRAS inhibitor for cancerous cells; designed for molecular recognition and for specific reaction with Cys12 in mutated malignant cells.
Figure 15.
Figure 15.
6-Aminonicotinamide 40, a potential fragment for FBDD of competitive G6PD inhibitors.
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