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.

Effects of physical activity on menopausal symptoms, psychosomatic factors and well-being among working women in England: A path analysis.

Background: Research to date suggests that physical activity (PA) can buffer menopausal symptoms and support well-being, but there is limited evidence on the link between PA and menopausal symptoms in the United Kingdom, and no study has assessed how PA affects well-being through menopausal symptoms and three psychosomatic factors (i.e. depression, anxiety and stress).

Professional Male Soccer Players' Perspectives of the Nutrition Culture Within an English Premier League Football Club: A Qualitative Exploration Using Bourdieu's Concepts of Habitus, Capital and Field.

Background And Aim: Professional soccer players' self-reported dietary intakes often do not meet recommended sport nutrition guidelines. Although behaviour change models have previously explored barriers and enablers to nutritional adherence, the cultural factors influencing players' nutritional habits also warrant investigation. Accordingly, we aimed to explore players' perceptions of the nutrition culture within the professional soccer environment.