Novel inhibitors of PARP1 and PARP14: design, synthesis, and potentiation of cisplatin efficacy in cancer.

Background: Poly(ADP-ribose) polymerase (PARP) is a superfamily of enzymes involved in cell survival. Both PARP1 and PARP14 are overexpressed in malignancies. No clinically approved PARP14 inhibitors are available, and PARP1 inhibitors are generally nonspecific, resulting in a need for a more diverse library of selective PARP1 and PARP14 inhibitors.

The potential association between PARP14 and SARS-CoV-2 infection (COVID-19).

Understanding the potential association between the poly (ADP-ribose) polymerase member 14 (PARP14) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may aid in understanding the host immunopathological response to the virus. PARP14 has an emerging role in viral infections, and this article considers its potential mechanisms for action in either a pro- or anti-viral manner. It is evident that more experimental work is required; however, PARP14 appears vital in controlling the interferon response to the SARS-CoV-2 infection and has potential roles in balancing the proinflammatory cytokines of the cytokine storm.

family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily.

Due to the conserved nature of the poly(ADP-ribose) polymerase (PARP) catalytic domain, the identification of unique residues is critical for the design of selective inhibitors. With inhibitors of the DNA-dependent PARP members already clinically approved, new efforts lie in discovering selective inhibitors for PARP5a and beyond. Targeting the noncatalytic domains, such as the macro2 and WWE domains may also provide a way to achieve selectivity.

Design, synthesis and evaluation of potential inhibitors for poly(ADP-ribose) polymerase members 1 and 14.

Poly(ADP-ribose) polymerase (PARP) members PARP1 and PARP14 belong to an 18-member superfamily of post-translational modifying enzymes. A library of 9 novel non-NAD analog amine compounds was designed, synthesized and evaluated for inhibitory activity against PARP1 and PARP14. Both studies and assays identified compound as a potential PARP1 inhibitor, inhibiting activity by 93 ± 2% (PARP14 inhibition: 0 ± 6%), and as a potential PARP14 inhibitor, inhibiting activity by 91 ± 2% (PARP1 inhibition: 18 ± 4%), at 10-μm concentration.

identification and activity of natural products as ADP-ribosyl transferase member 8 inhibitors.

ADP-ribosyl transferase member 8 (ARTD8) of the ARTD superfamily has been identified as a possible anti-cancer, antiviral and anti-inflammatory target. Pure actives from natural products with a documented anti-cancer activity were docked into the catalytic site of 3SMI.pdb using PyRx and AutoDock Vina.

Recent developments in PARP14 research.

This review aims to reflect upon the major developments in PARP14 research from late 2017 to early 2020. In doing so, this report will focus on the continual elucidation of PARP14's function including an emerging role in viral replication. This is in addition to other functional developments in cancer and inflammation, along with reflecting upon the leads in inhibitor design, including the increased attention toward the macrodomain.

From tea to treatment; epigallocatechin gallate and its potential involvement in minimizing the metabolic changes in cancer.

As the most abundant bioactive polyphenol in green tea, epigallocatechin gallate (EGCG) is a promising natural product that should be used in the discovery and development of potential drug leads. Due to its association with chemoprevention, EGCG may find a role in the development of therapeutics for prostate cancer. Natural products have long been used as a scaffold for drug design, as their already noted bioactivity can help accelerate the development of novel treatments.

Structure, Function and Inhibition of Poly(ADP-ribose)polymerase, Member 14 (PARP14).

Poly(ADP-ribose)polymerase, member 14 (PARP14, alternatively named ARTD8, BAL2, and COAST6) is an intracellular mono(ADP-ribosyl) transferase. PARP14 transfers a negatively charged ADP-ribose unit from a donor NAD+ molecule onto a target protein, post-translationally. PARP14's domain architecture consists of three macrodomains (Macro1, Macro2 and Macro3), a WWE domain and an ARTD (or catalytic domain).

A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists.

Elucidating details of the relationship between molecular structure and a particular biological end point is essential for successful, rational drug discovery. Molecular docking is a widely accepted tool for lead identification however, navigating the intricacies of the software can be daunting. Our objective was therefore to provide a step-by-step guide for those interested in incorporating contemporary basic molecular docking and homology modelling into their design strategy.

2-Oxo-1,2-dihydropyridinyl-3-yl amide-based GPa inhibitors: Design, synthesis and structure-activity relationship study.

Glycogen phosphorylase (GP), which plays a crucial role in the conversion of glycogen to glucose-1-phosphate, is a target for therapeutic intervention in diabetes. In this study, we report the design and synthesis of 29 new derivatives of 2-oxo-1,2-dihydro pyridin-3-yl amides, as potential inhibitors of GP. The hit rate (45%) was high with 13 compounds inhibiting GPa (between 33% at 4.

Synthesis and preliminary investigations into novel 1,2,3-triazole-derived androgen receptor antagonists inspired by bicalutamide.

A versatile and high yielding synthesis of novel androgen receptor (AR) antagonists is presented. Using this methodology, six 1,4-substituted-1,2,3-triazole derived bicalutamide mimics were synthesised in five steps and in isolated overall yields from 41% to 85%. Evaluation of these compounds for their anti-proliferative properties against androgen dependent (LNCaP) and independent (PC-3) cells showed promising IC50 values of 34-45 μM and 29-151 μM, respectively.

Synthesis, screening and docking of small heterocycles as glycogen phosphorylase inhibitors.

A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.

Preliminary investigations into triazole derived androgen receptor antagonists.

A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid.

Synthesis of new modified truncated peptides and inhibition of glycogen phosphorylase.

The first solution state structural analysis (NMR) of the C-terminal sequence of human G(L) that binds to glycogen phosphorylase a (GPa), PEWPSYLGYEKLGPYY-NH(2) (1), showed it to be in a random coil conformation. This was supported by molecular dynamics simulation (modelled in solution) using NAMD 2.6.