Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1.

Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis.

Same-day discharge following lumbar spine neural decompression.

Introduction: The concept of same-day discharge following lumbar spine surgery for neural elements decompression, introduced in the 1980 s, represents a significant paradigm shift in postoperative care, offering potential benefits in terms of efficiency, convenience, and cost-effectiveness. However, concerns regarding patient safety and complications have persisted. This study aims to assess same-day discharge rates following lumbar spine decompression surgery, identify preoperative predictors, and compare outcomes between same-day discharge and hospitalization.

Periprocedural clinical outcomes of revision hip arthroplasty: a multi-centric comparison of current strategies based on the NSQIP.

Introduction: Recent projections suggest a substantial rise in demand for revision total hip arthroplasties, emphasizing the need for optimized perioperative care. Various revision techniques, such as isolated acetabular or femoral component revisions and total replacements, have garnered attention. Further research is needed to establish the most effective strategies for improving clinical outcomes.

Predictors and risk factors of pulmonary embolism after total hip arthroplasty: an NSQIP study.

Introduction: Pulmonary embolism (PE) is a well-known contributor to morbidity after total hip arthroplasty (THA). Considerable efforts have been invested in reducing PE occurrence through pharmacological and perioperative interventions. Nonetheless, the effectiveness of these strategies in reducing the incidence and overall mortality associated with pulmonary embolism events remains a matter of debate.