In This Issue, Volume 13, Issue 12

Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma

Among the various NAD-derived inhibitors explored for treating pancreatic cancer, 6-aminonicotinamide (6AN) is a widely used heterocycle that is metabolized by an NAD salvage pathway to form 6-amino-NADP⁺. This metabolite inhibits 6-phosphogluconate dehydrogenase (6PDG) with moderate selectivity over other NADP⁺/NADPH-dependent enzymes and reverses chromatin methylation and gene expression in metastatic pancreatic ductal adenocarcinoma. However, dose-limiting neurotoxic effects render 6AN unacceptable for clinical progression. In this issue, Tsukamoto and colleagues from Johns Hopkins University disclose a novel prodrug strategy that masks the 2-aminonicotinic acid precursor as an ester. This strategy leads to antiproliferative activity, as indicated by histone methylation, and cell viability while also reducing neurotoxic effects in rat hippocampal neurons (DOI: 10.1021/acsmedchemlett.2c00404). Notably, metabolomic analyses showed that, upon entry into a cell, the leading prodrugs undergo ester hydrolysis and bioconversion to generate the active compound 6-amino-NADP⁺ via the Preiss–Handler pathway, which is overactive in pancreatic cancers and which differs from the previously exploited NAD salvage pathway. Thus, the selective activation of the prodrug in carcinoma cells, combined with the low activity level of the Preiss–Handler pathway in neurons, might contribute to the improved in vitro therapeutic window. Though ADMET characterization remains to be conducted, future studies will hopefully establish whether the promising prodrug strategy that exploits an alternate biosynthetic activation pathway will ultimately translate to providing in vivo benefits.

Structure–Activity Relationship Study of Tertiary Alcohol Hsp90α-Selective Inhibitors with Novel Binding Mode

The 90 kDa heat shock chaperone proteins (Hsp90) fold and activate client proteins associated with all 10 hallmarks of cancer, and nearly 20 Hsp90 inhibitors have reached clinical trials for the treatment of various cancers. These candidates, however, have all failed in the clinic because of unacceptable toxicities that likely arise from the pan-inhibition of all four Hsp90 isoforms (Hsp90α, Hsp90β, Trap1, and GRP94), which disrupts proper folding of many essential proteins. In contrast, isoform-selective inhibition has the potential to block the function of a subset of oncogenic proteins while minimizing pan-interference with protein homeostasis. Specifically, the stress-inducible Hsp90α isoform resides in both cytosolic and extracellular compartments and regulates the folding of several surface receptors, extracellular clients, and regulators of cell signaling. Further, this isoform is associated with aggressive cancer phenotypes, which suggests that the selective inhibition of Hsp90α should reduce the progression of cancers that rely on Hsp90α-dependent client proteins. In this issue, Blagg (University of Notre Dame), Matts (Oklahoma State University), and co-workers exploit crystallographic information to guide the design of Hsp90α-selective inhibitors (DOI: 10.1021/acsmedchemlett.2c00327). Notably, the team identifies previously underexploited pockets and contacts to generate Hsp90α-selective inhibitors. Their lead inhibitors can induce a novel conformational change in Hsp90α, leading to >300-fold selectivity over Trap1 and GRP94 and >13-fold selectivity over the Hsp90β isoform, which has 95% homology and differs by just two amino acids in the active site. Though the lead inhibitors do not manifest significant antiproliferative activity, improved analogs should provide opportunities to develop potent isoform-selective Hsp90α-selective inhibitors to explore basic cancer biology, synergistic therapies, and/or synthetic lethal combinations of therapeutics with Hsp90α-selective inhibitors.

Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action

The GPCRs GPR40 and GRP120, also known as free fatty acid receptors (FFARs) 1 and 4, play important roles in glucose and energy homeostasis and have been long targeted for treating type 2 diabetes mellitus (T2DM). Notably, orthosteric agonists of FFAR1 have shown clinical efficacy, though both the clinical candidates and next-generation agonists displayed hepatic and pancreatic β-cell toxicities, respectively, which are likely linked to the highly lipophilic scaffolds required to engage the orthosteric site. Additionally, dual FFAR1/FFAR4 agonists have also shown preclinical promise in decreasing insulin resistance and ultimately β-cell failure, though the previously reported dual agonists require further development. In this issue, Frimurer and collaborators at the University of Copenhagen and King’s College London report a series of novel allosteric agonists that activate both FFAR1 (full agonist) and FFAR4 (partial agonist) with nanomolar potency (DOI: 10.1021/acsmedchemlett.2c00160). Notably, engagement of the allosteric site enables activation by less lipophilic scaffolds that are not tolerated at the hydrophobic orthosteric site that normally recognizes medium- and long-chain fatty acids. Preliminary ADME studies indicate that the lead compounds only display modest metabolic stability, and future lead optimization will be required to deliver probes for in vivo studies that may ultimately validate this allosteric site for therapeutic intervention.