Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 ().

Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an Enabled Drug Discovery Platform.

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S.

Concentration of spending and share of specialty drug spending in Medicare Part D over a 10-year period.

Background: In 2021, Medicare Part D gross prescription drug spending amounted to $216 billion, a number that has more than doubled over the last 10 years. Spending in Medicare Part D is concentrated on a small number of drugs, and spending on specialty drugs has increased in recent years. However, the extent to which concentration in Part D spending has changed over time and the drivers of this change have not been described.

Patients follow four clusters of participation in physical exercise after an ACL injury. Results from the NACOX cohort study.

Objectives: To explore how participation in physical exercise (PE) changes over time after an anterior cruciate ligament (ACL) injury. Additionally, to identify factors associated with participation in PE by analyzing longitudinal data.

Design: An explorative analysis of the NACOX study, a prospective multicenter cohort study.

Identification of sentinel lymph node macrometastasis in breast cancer by deep learning based on clinicopathological characteristics.

The axillary lymph node status remains an important prognostic factor in breast cancer, and nodal staging using sentinel lymph node biopsy (SLNB) is routine. Randomized clinical trials provide evidence supporting de-escalation of axillary surgery and omission of SLNB in patients at low risk. However, identifying sentinel lymph node macrometastases (macro-SLNMs) is crucial for planning treatment tailored to the individual patient.