Balancing Properties with Carboxylates: A Lead Optimization Campaign for Selective and Orally Active CDK9 Inhibitors.

Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration.

A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies.

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically.

Discovery of ABBV-4083, a novel analog of Tylosin A that has potent anti-Wolbachia and anti-filarial activity.

There is a significant need for improved treatments for onchocerciasis and lymphatic filariasis, diseases caused by filarial worm infection. In particular, an agent able to selectively kill adult worms (macrofilaricide) would be expected to substantially augment the benefits of mass drug administration (MDA) with current microfilaricides, and to provide a solution to treatment of onchocerciasis / loiasis co-infection, where MDA is restricted. We have identified a novel macrofilaricidal agent, Tylosin A (TylA), which acts by targeting the worm-symbiont Wolbachia bacterium.

CroFab reconstitution in various media: an in vitro solubility study.

Background: We investigated the solubility of Crotalidae Polyvalent Ovine Immune Fab antivenom (CroFab, Savage Labs and Protherics Inc., Brentwood, TN, USA) in solutions not listed in the Food and Drug Administration (FDA)-approved product package insert. We also assessed whether adsorption to plastic tubing occurs with CroFab preparations.

A pilot study of occupational envenomations in North American zoos and aquaria.

Objective: To characterize occupational envenomations from exotic and native creatures, we surveyed North American zoos and aquaria.

Methods: Survey questionnaires were mailed to curators at 216 zoos/aquaria which are accredited by the Association of Zoos and Aquariums (AZA) and listed on the AZA website. Reptile curators were asked to complete the zoo surveys.

Left ventricular assist device implantation via left thoracotomy: alternative to repeat sternotomy.

Repeat sternotomy for left ventricular assist device insertion may result in injury to the right heart or patent coronary grafts, complicating intraoperative and postoperative management. In 4 critically ill patients, left thoracotomy was used as an alternative to repeat sternotomy. Anastomosis of the outflow conduit to the descending thoracic aorta provided satisfactory hemodynamic support.