Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties.

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.

Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors.

Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.

The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited.

Epidemiological Review of Francisella Tularensis: A Case Study in the Complications of Dual Diagnoses.

Introduction: Tularemia is a rare but potentially fatal disease that develops in numerous wild and domestic animals, including lagomorphs, rodents, cats, and humans.  Francisella tularensis bacterium, the causative agent of tularemia, was identified by veterinary personnel at Fort Riley, Kansas during a routine post-mortum evaluation of a domestic feline. However, before formal diagnosis was confirmed, the sample was sent and prepared for rabies testing at the Department of Defense (DoD) U.

Functionally diverse nucleophilic trapping of iminium intermediates generated utilizing visible light.

Our previous studies into visible-light-mediated aza-Henry reactions demonstrated that molecular oxygen played a vital role in catalyst turnover as well as the production of base to facilitate the nucleophilic addition of nitroalkanes. Herein, improved conditions for the generation of iminium ions from tetrahydroisoquinolines that allow for versatile nucleophilic trapping are reported. The new conditions provide access to a diverse range of functionality under mild, anaerobic reaction conditions as well as mechanistic insights into the photoredox cycle.

Further validation of the MMPI-2 and MMPI-2-RF Response Bias Scale: findings from disability and criminal forensic settings.

The present study extends the validation of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) Response Bias Scale (RBS; R. O. Gervais, Y.

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition.

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.

Examination of the MMPI-2 restructured form (MMPI-2-RF) validity scales in civil forensic settings: findings from simulation and known group samples.

The current study examined the effectiveness of the MMPI-2 Restructured Form (MMPI-2-RF; Ben-Porath and Tellegen, 2008) over-reporting indicators in civil forensic settings. The MMPI-2-RF includes three revised MMPI-2 over-reporting validity scales and a new scale to detect over-reported somatic complaints. Participants dissimulated medical and neuropsychological complaints in two simulation samples, and a known-groups sample used symptom validity tests as a response bias criterion.

The relation between symptom validity testing and MMPI-2 scores as a function of forensic evaluation context.

The association between scores on MMPI-2 scales and cognitive symptom validity test (SVT) failure was investigated in 127 criminal defendants evaluated for competency to stand trial, criminal responsibility, and drug dependence, and 141 personal injury and disability claimants. Results indicated that SVT failure was associated with exaggerated symptom presentation involving somatic complaints in civil litigants and more global exaggeration of psychopathology and somatic complaints in criminal defendants. Scores on the MMPI-2 Fake Bad Scale (FBS) were associated with SVT failure in both civil and criminal litigants, whereas scores on the MMPI-2 F(P) scale were associated with SVT failure in criminal defendants, but not in civil plaintiffs.