In This Issue, Volume 12, Issue 4

Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction

Histone deacetylases (HDACs) enzymatically regulate gene transcription of proteins through the cleavage of their N-acetylated lysine residues and remodeling of chromatin. While several FDA-approved HDAC inhibitors (HDACis) target proliferating tumor cells of certain cancers, the putatively required HDACi pharmacophoric elements of these drugs that involve enzymatic zinc atom-engagement also induce mutagenicity, toxicity or present pharmacokinetic hurdles that are challenging to overcome, thereby limiting their development for broader application. In this Featured letter (DOI: 10.1021/acsmedchemlett.1c00074), Beshore and co-workers report on the development of natural-product-inspired, indole-acetamide-based HDAC inhibitors that, by X-ray crystallographic evidence, do not coordinate to the catalytic zinc atom. Nonetheless, members of the structural class showed potent biochemical enzymatic inhibition and cell-based efficacy that is similar to that of marketed HDAC inhibitor drugs containing traditional zinc-binding moieties. The authors explored structure–activity relationships that probed binding capability, HDAC isozyme selectivity, and efficacy in cell models evaluating HIV latency reversal. The resulting lead compound 19 was profiled for off-target liability, was shown to be nonmutagenic, and exhibited promising pharmacokinetic properties. Based on the collective results, this report marks an important leap in the understanding of HDAC inhibitor development, thus reconceptualizing a pharmacophoric HDAC inhibition model that traditionally requires a metal binding structural moiety.

Discovery of the First Orally Available, Selective KNa1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series

The sodium-activated potassium channel K_Na1.1 is expressed throughout the central nervous system and is encoded by the KCNT1 gene. Mutations in KCNT1 that confer enhanced protein function are associated with multiple forms of drug-resistant infant and childhood seizure disorder. Therapeutics are urgently sought to address inadequate efficacy and target selectivity associated with investigational drugs. To discover novel K_Na1.1 channel modulators, Griffin and co-workers (DOI: 10.1021/acsmedchemlett.0c00675) screened a custom commercial compound library to reveal oxadiazole appended pyrazole 5-carboxamides as a hit scaffold. Structure–activity relationships based on human K_Na1.1 channel inhibition were explored across four scaffold regions in a dose response format with attention paid to potency, lipophilicity, solubility, stereochemical influence, clearance, and validation of response on the equivalent mouse K_Na1.1 channel. The best candidate resulting from this effort was further profiled against human KCNT1 variants that result in a gain of function, along with an 80-member off-target panel that included other ion channels for which cross-activity may be of concern. Pharmacokinetic evaluation in mice showed reasonable brain exposure and complementary parameters that permitted oral dosing in a mouse model of epileptic encephalopathy. The authors show that mice dosed orally with the candidate compound showed reduced seizure activity compared to control mice, suggesting that this class of compounds may provide insights into the development of therapeutic options for severe forms of epileptic syndromes in children.

Synthesis, Inhibitory Activity, and In Silico Modeling of Selective COX-1 Inhibitors with a Quinazoline Core

Cyclooxygenase (COX) isozymes, COX-1 and COX-2, are integral to inflammatory mechanisms, and their inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) treats pain, fever, and inflammation. While classical NSAIDs are unselective between the two isozymes, newer agents have focused on targeting COX-2 selectively for these therapeutic properties. While some selective COX-1 inhibitors have been developed, interest in selective COX-1 inhibitors with appropriate pharmacokinetic characteristics has been renewed as the roles of this enzyme in multiple cancers, cardiovascular and neurological inflammatory processes have been better elucidated. With the intent of designing selective COX-1 inhibitors with improved properties, Dvorakova and co-workers (DOI: 10.1021/acsmedchemlett.1c00004) generated structurally inspired analogues of quinazoline-based third generation NSAIDs such as fluproquazone and proquazone but which feature augmented structural elements intended to exploit key differences between the binding pockets of COX-1 and COX-2. After multiple rounds of structure–activity relationship development and evaluation of COX inhibition and selectivity, a styrene-containing aminoquinazoline 9b resulted that potently and selectively inhibited COX-1 through a substrate competitive mechanism. In silico docking of the analogues was performed to provide a rationale for the observed selectivity and suggests that selective COX-1 inhibition may be achieved and probed for therapeutic advantage.