Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma.

Background And Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target.

Evaluation of Therapeutics for Severely Debilitating or Life-Threatening Diseases or Conditions: Defining Scope to Enable Global Guidance Development.

A significant regulatory gap exists to facilitate global development of therapeutics for nononcology severely debilitating or life-threatening diseases or conditions (SDLTs). In a 2017 publication, a streamlined approach to the development of treatments for SDLTs was proposed to facilitate earlier and continued patient access to new, potentially beneficial therapeutics. However, a major hindrance to broad adoption of this streamlined approach has been the lack of universally accepted, objective criteria to define SDLTs.

In vitro secondary pharmacological profiling: An IQ-DruSafe industry survey on current practices.

Introduction: In 2015, IQ DruSafe conducted a survey of its membership to identify industry practices related to in vitro off target pharmacological profiling of small molecules.

Methods: An anonymous survey of 20 questions was submitted to IQ-DruSafe representatives. Questions were designed to explore screening strategies, methods employed and experience of regulatory interactions related to in vitro secondary pharmacology profiling.

Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database.

The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies.

Proteasome inhibitors bortezomib and carfilzomib used for the treatment of multiple myeloma do not inhibit the serine protease HtrA2/Omi.

The proteasome inhibitor bortezomib is associated with the development of peripheral neuropathy in patients, but the mechanism by which bortezomib can induce peripheral neuropathy is not fully understood. One study suggested that off-target inhibition of proteases other than the proteasome, particularly HtraA2/Omi, may be the underlying mechanism of the neuropathy. The same study also concluded that carfilzomib, a second proteasome inhibitor that is associated with less peripheral neuropathy in patients than bortezomib, showed no inhibition of HtrA2/Omi.

MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors.

The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors.

Use of animals for toxicology testing is necessary to ensure patient safety in pharmaceutical development.

There is an active debate in toxicology literature about the utility of animal testing vis-a-vis alternative in vitro paradigms. To provide a balanced perspective and add to this discourse it is important to review the current paradigms, explore pros and cons of alternatives, and provide a vision for the future. The fundamental goal of toxicity testing is to ensure safety in humans.

Exclusive antagonism of the α4 β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates.

Background: Biological therapies that antagonize specific molecules have demonstrated efficacy in inflammatory bowel diseases, but infections resulting from systemic immunosuppression underscore the need for safer therapies. The objective of this investigation was to determine if antagonism of the α(4) β(7) integrin would exclusively yield gut-selective antiinflammatory activity in primates.

Methods: A series of experiments were conducted to investigate potential intra- and extraintestinal effects in healthy nonhuman primates dosed repeatedly with the α(4) β(7) -exclusive antagonist vedolizumab (former versions: MLN0002, MLN02, LDP-02) for 4, 13, and 26 weeks.

Identification and characterization of amino-piperidinequinolones and quinazolinones as MCHr1 antagonists.

Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.

Transgenic mice with cardiac-specific over-expression of MLK7 have increased mortality when exposed to chronic beta-adrenergic stimulation.

Mixed lineage kinase 7 (MLK7) is a recently identified mitogen-activated protein kinase kinase kinase with enriched expression in skeletal muscle and heart. When over-expressed in cardiac myocytes, MLK7 activates both the p38 and c-Jun N-terminal kinase (JNK) stress-activated pathways and induces a cellular phenotype characteristic of cardiac hypertrophy, including a fetal gene expression pattern and increased protein synthesis. We sought to determine the effect of MLK7 on cardiac function in vivo by generating transgenic (Tg) mice with cardiac restricted over-expression of the enzyme.

Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins.

Angiotensin converting enzyme related carboxypeptidase (ACE2) is a recently discovered homolog of angiotensin converting enzyme with tissue-restricted expression, including heart, and the capacity to cleave angiotensin peptides. We tested the hypothesis that cardiac ACE2 activity contributes to features of ventricular remodeling associated with the renin-angiotensin system by generating transgenic mice with increased cardiac ACE2 expression. These animals had a high incidence of sudden death that correlated with transgene expression levels.

Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy.

Objective: Exogenous catecholamine exposure has been associated with p38 mitogen-activated protein kinase (MAPK) and cardiac hypertrophy. In this study, we investigated the regulation of p38 MAPK in cardiac remodeling elicited by endogenous adrenergic mechanisms.

Methods: Transgenic male and female mice with fourfold phospholamban (PLB) overexpression exhibited enhanced circulating norepinephrine (NE), as a physiological compensatory mechanism to attenuate PLB's inhibitory effects.

Hypertrophy and functional alterations in hyperdynamic phospholamban-knockout mouse hearts under chronic aortic stenosis.

Objective: To determine whether the hyperdynamic phospholamban-knockout hearts are capable of withstanding a chronic aortic stenosis.

Methods: The transverse section of the aorta was banded in phospholamban-knockout and their isogenic wild-type mice, which were followed with echocardiography in parallel, along with sham-operated mice, before and at 2.5, 5 and 10 weeks after surgery.