3 research outputs found
Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase
Fragment-based
drug design was successfully applied to maternal embryonic leucine
zipper kinase (MELK). A low affinity (160 μM) fragment hit was
identified, which bound to the hinge region with an atypical binding
mode, and this was optimized using structure-based design into a low-nanomolar
and cell-penetrant inhibitor, with a good selectivity profile, suitable
for use as a chemical probe for elucidation of MELK biology
Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2‑Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery
KEAP1
is the key regulator of the NRF2-mediated cytoprotective
response, and increasingly recognized as a target for diseases involving
oxidative stress. Pharmacological intervention has focused on molecules
that decrease NRF2-ubiquitination through covalent modification of
KEAP1 cysteine residues, but such electrophilic compounds lack selectivity
and may be associated with off-target toxicity. We report here the
first use of a fragment-based approach to directly target the KEAP1
Kelch–NRF2 interaction. X-ray crystallographic screening identified
three distinct “hot-spots” for fragment binding within
the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment
hit to molecules with nanomolar affinity for KEAP1 while maintaining
drug-like properties. This work resulted in a promising lead compound
which exhibits tight and selective binding to KEAP1, and activates
the NRF2 antioxidant response in cellular and <i>in vivo</i> models, thereby providing a high quality chemical probe to explore
the therapeutic potential of disrupting the KEAP1–NRF2 interaction
Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors
Herein, we describe the discovery of potent and highly
selective
inhibitors of both CDK4 and CDK6 via structure-guided optimization
of a fragment-based screening hit. CDK6 X-ray crystallography and
pharmacokinetic data steered efforts in identifying compound <b>6</b>, which showed >1000-fold selectivity for CDK4 over
CDKs 1 and 2 in an enzymatic assay. Furthermore, <b>6</b> demonstrated
in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1
mouse xenograft model