Temporal Dynamics of Cardiovascular Risk in Patients with Chronic Obstructive Pulmonary Disease During Stable Disease and Exacerbations: Review of the Mechanisms and Implications.

Introduction: Exacerbations of chronic obstructive pulmonary disease (COPD) are risk factors for severe cardiovascular (CV) events, with the risk remaining significantly elevated long after the symptomatic phase of the exacerbation. The pathophysiology underpinning the relationship between acute events of both COPD and CV diseases has been understudied. Our objectives were to review the mechanisms by which COPD exacerbations increase the risk of CV events and understand the temporality of this risk.

Mapping Ligand Interactions of Bromodomains BRD4 and ATAD2 with FragLites and PepLites─Halogenated Probes of Druglike and Peptide-like Molecular Interactions.

The development of ligands for biological targets is critically dependent on the identification of sites on proteins that bind molecules with high affinity. A set of compounds, called FragLites, can identify such sites, along with the interactions required to gain affinity, by X-ray crystallography. We demonstrate the utility of FragLites in mapping the binding sites of bromodomain proteins BRD4 and ATAD2 and demonstrate that FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites and key interactions.

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity.

The Underestimated and Overlooked Burden of Diarrhea and Constipation in Cancer Patients.

Purpose Of Review: This review aims to summarize and discuss the diverse causes of two major gastrointestinal dysfunction symptoms, diarrhea and constipation, in cancer patients. We also discuss short- and long-term clinical, economic, and humanistic consequences, including the impact on cancer treatment regimens and patient quality of life, highlighting the limitations of the literature.

Recent Findings: Diarrhea and constipation as a result of cancer and its treatment can risk the success of anti-cancer therapies by requiring treatment delay or withdrawal, and imposes a substantial humanistic burden in patients with cancer.

Cyclizations and fragmentations in the alkylation of 6-chloro-5-hydroxy-4-aminopyrimidines with aminoalkyl chlorides.

Substituted aminopyrimidines are an important class of compounds, in part because they frequently show biological activity. Facile synthesis of polysubstituted aminopyrimidines is highly desirable for the synthesis of screening libraries. We describe a route to 4,6-diamino-5-alkoxypyrimidines via a SAr-alkylation-SAr sequence from readily available 4,6-dichloro-5-methoxypyrimidine, which allows the synthesis of such compounds with regiochemical control.

An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase.

NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome.

Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4.

Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α.

Recent advances in CDK inhibitors for cancer therapy.

Inhibition of CDKs is an attractive approach to cancer therapy due to their vital role in cell growth and transcription. Pan-CDK inhibitors have shown some clinical benefit, and trials are ongoing. Selective CDK4 and CDK6 inhibitors have been licensed for the treatment of hormone responsive, RB-positive breast cancer in combination with antihormonal agents.

Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach.

ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails.