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. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

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. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

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. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppresses tumor growth in vivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.

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.S. Army Public Health Command Central (PHC-C), Food Analysis and Diagnostic Laboratory (FADL).  This case report provides insight on how veterinarian staff and laboratory personnel can clinically manage esoteric, unexplained, or post-mortum examinations.  The epidemiologic characteristics of tularemia, F. tularensis as an organism of military interest, potential laboratory management of F. tularensis, and clinical findings on a case of feline tularemia are discussed. It further raises questions as to whether or not dead animals should be treated as sentinels and be pre-screened for select agents, especially in instances of dual diagnoses. METHODS: A necropsy was performed on the cat by the Fort Riley veterinarian, DNA extraction and PCR analyses were conducted by FADL microbiologists, histology and immunohistology analyses were conducted by the Kansas State Veterinary Diagnostic Laboratory, and feline tissue and blood were sent to the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) for confirmatory testing and strain identification of tularemia. RESULTS: Tularemia was identified in the spleen of the cat by the Fort Riley veterinarian and during the histological sampling of the spleen by the Kansas State Veterinary Diagnostic Laboratory.  A specific subsequent real-time polymerase chain reaction (RT-PCR) in vitro diagnostic detection of target DNA sequences of F. tularensis was conducted by the FADL microbiologists using a Joint Biological Agent Identification and Diagnostic System (JBAIDS) Tularemia Detection Kit to detect a presumptive qualitative result to detect tularemia in feline and blood samples.   USAMRIID also performed RT-PCR and identified genomic DNA from F. tularensis Type A, (SPL15.013.02), thus confirming the FADL's initial presumptive result of F. tularensis.  USAMRIID attempted to culture F. tularensis from three samples (swab, feline tissue, and transfer pipette tip), but no growth consistent with F. tularensis was observed on the cysteine heart agar with sheep blood and antibiotics (CHAB) and chocolate (CHOC) plates. DISCUSSIONS: Our case study of a dual diagnosis of presumptive F. tularensis and possible rabies exposure transmission from a pet cat to its owner provides insight on how veterinarian staff and laboratory personnel can clinically manage esoteric, unexplained, or post-mortum examinations.  Our case study also demonstrates the obligation for cooperation between animal health, human health, and public health professionals in the management of zoonotic diseases.

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. S. Ben-Porath, D. B. Wygant, & P. Green, 2007) in separate forensic samples composed of disability claimants and criminal defendants. Using cognitive symptom validity tests as response bias indicators, the RBS exhibited large effect sizes (Cohen's ds = 1.24 and 1.48) in detecting cognitive response bias in the disability and criminal forensic samples, respectively. The scale also added incremental prediction to the traditional MMPI-2 and the MMPI-2-RF overreporting validity scales in the disability sample and exhibited excellent specificity with acceptable sensitivity at cutoffs ranging from 90T to 120T. The results of this study indicate that the RBS can add uniquely to the existing MMPI-2 and MMPI-2-RF validity scales in detecting symptom exaggeration associated with cognitive response bias.

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. Results indicated large effect sizes for the MMPI-2-RF validity scales, including a Cohen's d of .90 for Fs in a head injury simulation sample, 2.31 for FBS-r, 2.01 for F-r, and 1.97 for Fs in a medical simulation sample, and 1.45 for FBS-r and 1.30 for F-r in identifying poor effort on SVTs. Classification results indicated good sensitivity and specificity for the scales across the samples. This study indicates that the MMPI-2-RF over-reporting validity scales are effective at detecting symptom over-reporting in civil forensic settings.

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. These results support the utility of the FBS as an indicator of non-credible presentation of somatic and cognitive complaints in both civil and criminal forensic psychological assessments, and indicate that the lack of association between the MMPI-2 infrequency scales and SVT failure is limited to civil forensic settings.