Selective and Potent PROTAC Degraders of c-Src Kinase.

Using dasatinib linked to E3 ligase ligands, we identified a potent and selective dual Csk/c-Src PROTAC degrader. We then replaced dasatinib, the c-Src-directed ligand, with a conformation-selective analogue that stabilizes the αC-helix-out conformation of c-Src. Using the αC-helix-out ligand, we identified a PROTAC that is potent and selective for c-Src. We demonstrated a high degree of catalysis with our c-Src PROTACs. Using our c-Src PROTACs, we identified pharmacological advantages of c-Src degradation compared to inhibition with respect to cancer cell proliferation.

QSAR via multisite λ-dynamics in the orphaned TSSK1B kinase.

Multisite λ-dynamics (MSλD) is a novel method for the calculation of relative free energies of binding for ligands to their targeted receptors. It can be readily used to examine a large number of molecules with multiple functional groups at multiple sites around a common core. This makes MSλD a powerful tool in structure-based drug design. In the present study, MSλD is applied to calculate the relative binding free energies of 1296 inhibitors to the testis specific serine kinase 1B (TSSK1B), a validated target for male contraception. For this system, MSλD requires significantly fewer computational resources compared to traditional free energy methods like free energy perturbation or thermodynamic integration. From MSλD simulations, we examined whether modifications of a ligand at two different sites are coupled or not. Based on our calculations, we established a quantitative structure-activity relationship (QSAR) for this set of molecules and identified a site in the ligand where further modification, such as adding more polar groups, may lead to increased binding affinity.

Rare presentation of small bowel intussusception in childhood.

Small bowel intussusception complicated simultaneously by volvulus in an older child is rare but clinically significant, necessitating urgent operative management. We report a local case of jejuno-jejunal intussusception complicated by volvulus and bowel infarction in a 9-year-old Chinese girl, with diagnosis made on preoperative computed tomography and confirmed at laparotomy. An intestinal polyp as the lead point for intussusception was identified operatively.

Pseudoaneurysm and intramuscular haematoma after dynamic hip screw fixation for intertrochanteric femoral fracture: a case report.

We report the case of an 83-year-old woman who developed a pseudoaneurysm of the profunda femoris artery after dynamic hip screw fixation for an intertrochanteric femoral fracture. 23 days after the fixation, radiological investigations including colour Doppler ultrasonography and computed tomographic angiography identified a pseudoaneurysm surrounded by a large intramuscular haematoma close to the profunda femoris. The patient underwent emergency evacuation and was under intensive care for 3 days and was discharged 6 weeks later, with no complications. At one-year follow-up, the wound and fracture had healed, but the patient was confined to a wheelchair. A high index of clinical suspicion and radiological imaging are necessary for making the diagnosis.