S. Knapp

Modulating pseudokinase conformation from the ATP-binding site

SUMMARY Pseudokinase domains (PsKDs) mediate key signaling processes involved in human disease. Despite transformative success in targeting catalytically active protein kinases, drug development for pseudokinases has lagged behind. Although they lack catalytic activity, pseudokinases are conformationally dynamic and ar...

The structural basis for LRRK2’s activation and autoinhibition

Using cryo-EM, biochemical reconstitution, and cell-based assays, it is shown that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition.

Accelerate Your Science: Direct-to-Biology Strategies in Medicinal Chemistry

Direct-to-biology (D2B) is a powerful strategy that accelerates early drug discovery. It enables compounds to be synthesized in miniaturized formats and evaluated directly as crude reaction mixtures. This bypasses the need for purification during the initial design-make-test cycle. Advances in robust synthetic methodol...

Macrocyclization of Broad-Spectrum Kinase Inhibitor Bosutinib Leads to Potent and Selective Quinoline-Based HIPK4 Inhibitor AZ137

A rational design strategy utilizing macrocyclization of a bosutinib-based scaffold provides a foundational framework for the validating HIPK4 as a therapeutic target and a high-quality resource to elucidate its roles in normal physiology and disease.

Utilization of Functional Degradation Pathways for the Characterization of Ubiquitin-Proteasome System Tool Compounds.

Macrocyclization of Broad-Spectrum Kinase Inhibitor Bosutinib Leads to Potent and Selective Quinoline-Based HIPK4 Inhibitor AZ137

Homeodomain-interacting protein kinase 4 (HIPK4) remains an understudied member of the dark kinome. While genetic knockout studies suggest its involvement in spermiogenesis and cutaneous squamous cell carcinoma, whether these cellular functions can be recapitulated by pharmacological inhibition remains to be determin...

USP22 is a novel vulnerability regulating MEIS1 protein abundance and gene transcription in KMT2Ar acute leukemia.

A genome-wide CRISPR/Cas9 screen in a KMT2Ar B-cell acute lymphoblastic leukemia cell line identified the deubiquitinase USP22 as a novel regulator of MEIS1 protein stability, that could potentially be exploited as a therapeutic target in the future in KMT2Ar leukemias.

Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy

It is found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models, and restores cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.