Addressing hERG activity while maintaining favorable potency, selectivity and pharmacokinetic properties of PPARδ modulators.

One of the most commonly used strategies to reduce hERG (human ether-a-go-go) activity in the drug candidates is introduction of a carboxylic acid group. During the optimization of PPARδ modulators, some of the compounds containing a carboxylic acid were found to inhibit the hERG channel in a patch clamp assay. By modifying the basicity of the imidazole core, potent and selective PPARδ modulators that do not inhibit hERG channel were identified. Some of the modulators have excellent pharmacokinetic profiles in mice.

Correction to "Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)".

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00287.].

Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD).

The X-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.

Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy.

Mitophagy is one of the processes that cells use to maintain overall health. An E3 ligase, parkin, ubiquitinates mitochondrial proteins prior to their degradation by autophagasomes. USP30 is an enzyme that de-ubiquitinates mitochondrial proteins; therefore, inhibiting this enzyme could foster mitophagy. Herein, we disclose the structure-activity relationships (SAR) within a novel series of highly selective USP30 inhibitors. Two structurally similar compounds, MF-094 (a potent and selective USP30 inhibitor) and MF-095 (a significantly less potent USP30 inhibitor), serve as useful controls for biological evaluation. We show that MF-094 increases protein ubiquitination and accelerates mitophagy.

Author Correction: Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

In the originally published version of this Letter, the authors Arthur F. Kluge, Michael A. Patane and Ce Wang were inadvertently omitted from the author list. Their affiliations are: I-to-D, Inc., PO Box 6177, Lincoln, Massachusetts 01773, USA (A.F.K.); Mitobridge, Inc. 1030 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (M.A.P.); and China Novartis Institutes for BioMedical Research, No. 4218 Jinke Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai 201203, China (C.W.). These authors contributed to the interpretation of results and design of compounds. In addition, author 'Edward A. Kesicki' was misspelled as 'Ed Kesicki'. These errors have been corrected online.

Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.

p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.

Highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulator demonstrates improved safety profile compared to GW501516.

Compound 1 regulates significantly fewer genes than the PPARδ modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns.

Novel highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulators with pharmacokinetic properties suitable for once-daily oral dosing.

Optimization of benzamide PPARδ modulator 1 led to (E)-6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)-4-methylhex-4-enoic acid (18), a potent selective PPARδ modulator with significantly improved exposure in multiple species following oral administration.

Targeted covalent drugs of the kinase family.

In the past decade tremendous progress has been made toward a new class of therapeutics termed 'targeted covalent drugs', in which structure-based approaches are employed to create small molecules that inactivate their protein target through targeted covalent attachment to a specific cysteine. In the kinase field, this approach is demonstrating promise in overcoming the potency, selectivity, and efficacy challenges currently faced by reversible kinase inhibitors, with several advancing into late stage clinical testing. This design paradigm has been successfully applied to making drug candidates for epidermal growth factor receptor (EGFR), Her2, and Bruton's tyrosine kinase (Btk). Here we review recent pre-clinical and clinical advances with targeted covalent kinase inhibitors, and the potential for broader application of the approach.

Acylating drugs: redesigning natural covalent inhibitors.

Structural modification of naturally occurring beta-lactams and beta-lactones is a highly effective strategy for generating drugs for treating bacterial infections, cancer, obesity, and hyperlipidemia. These drugs acylate catalytic amino acids (serine, threonine, or cysteine) in enzyme targets such as penicillin-binding proteins (PBPs), beta-lactamases, lipases, HMG-CoA reductase, fatty acid synthetase, and the 20S proteasome. Optimally performing drugs combine features of high target affinity, chemoselective reactivity, and high stability of the acylated target protein. This review provides a perspective on these two classes of acylating agents and summarizes recent advances in mechanism and structure-based design of acylating drugs.

A three-hybrid approach to scanning the proteome for targets of small molecule kinase inhibitors.

In this study, we explored the application of a yeast three-hybrid (Y3H)-based compound/protein display system to scanning the proteome for targets of kinase inhibitors. Various known cyclin-dependent kinase (CDK) inhibitors, including purine and indenopyrazole analogs, were displayed in the form of methotrexate-based hybrid ligands and deployed in cDNA library or yeast cell array-based screening formats. For all inhibitors, known cell cycle CDKs as well as novel candidate CDK-like and/or CDK-unrelated kinase targets could be identified, many of which were independently confirmed using secondary enzyme assays and affinity chromatography. The Y3H system described here may prove generally useful in the discovery of candidate drug targets.

Antifungal activity of a Candida albicans GGTase I inhibitor-alanine conjugate. Inhibition of Rho1p prenylation in C. albicans.

An alanine conjugate of a Candida albicans geranylgeranyl transferase I inhibitor was synthesized to facilitate its uptake into the fungal cell. The antifungal activity of CaGGTase-Ala conjugate is demonstrated. It is also shown that the CaGGTase-Ala conjugate affects prenylation of endogenous Rho1p, but has no effect on prenylation of endogenous Ras1p.