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.

A Computational Physics-based Approach to Predict Unbound Brain-to-Plasma Partition Coefficient, K.

The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small-molecule central nervous system (CNS) drugs is characterized by a high unbound brain/plasma ratio (K). While various medicinal chemistry strategies and models have been reported to improve BBB penetration, they have limited application in predicting K directly.

Simultaneous Measurement of Strain and Temperature Distributions Using Optical Fibers with Different GeO and BO Doping.

Compensating for the effects of temperature is a crucial issue in structural health monitoring when using optical fiber sensors. This study focused on the change in sensitivity due to differences in GeO2 and B2O3 doping and then verified the accuracy when measuring the strain and temperature distributions simultaneously. Four types of optical fiber sensors were utilized to measure the strain and temperature in four-point bending tests, and the best combination of the sensors resulted in strain and temperature errors of 28.