Identifying and evaluating understudied protein kinases using biological and chemical criteria
Shown is a comparison of biologically defined “dark” and chemically defined “un-/underexplored” protein kinases that are mapped on a phylogenetic tree representation of the human kinome.
Unravelling the potency of the 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile scaffold with S-arylamide hybrids as PIM-1 kinase inhibitors: synthesis, biological activity and in silico studies
Discovery of new PIM-1 inhibitors with the 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile scaffold with S-arylamide hybrids.
Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α
The first degrader of an ER-resident protein (IRE1α) is described with properties more akin to a molecular glue than a traditional PROTAC, thus challenging the dogma of categorizing degrader modalities based on their physicochemical features.
Research Article
Lysine targeting covalent inhibitors of malarial kinase PfCLK3
A series of covalent PfCLK3 inhibitors targeting catalytic Lys394 were designed, synthesised, and evaluated as antimalarials, providing a novel strategy to combat malaria resistance.
Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors
Late-stage pyrazole functionalization was used to rapidly explore SAR and led to the identification of a potent HPK1 inhibitor.
Rational design and discovery of potent PROTAC degraders of ASK1: a targeted therapy in MASH
The first PROTAC degrader of ASK1, dASK1-VHL (60), was rationally designed and validated via in vitro assays and PK studies, demonstrating therapeutic efficacy in an MCD diet-induced MASH mouse model, underscoring its promise in metabolic diseases.
Design and synthesis of (E)-3-benzylideneindolin-2-one derivatives as potential allosteric inhibitors of Aurora A kinase
The compound AK34, derived from Tripolin A, shows a pronounced inhibitory effect on Aurora A kinase with high affinity (IC50 = 1.68 μM, KD = 216 nM). SAR and molecular docking indicate that these (E)-3-benzylideneindolin-2-one derivatives tend to act on an allosteric Site 3 predicted by AlloReverse.
Research Article
Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors
A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease.
Research Article
Ligand-centred phenotype-driven development of potent kinase inhibitors against oesophageal cancer
A ligand-centred strategy combined with phenotypic screening was used to develop novel antiproliferative inhibitors against oesophageal cancer and identified a lead compound that induces potent anticancer activity and inhibits Aurora kinase A.
Research Article
Discovery of selective LATS inhibitors via scaffold hopping: enhancing drug-likeness and kinase selectivity for potential applications in regenerative medicine
Using scaffold hopping aided by docking studies and AI-assisted metabolic stability predictions, we identified a novel LATS inhibitor with potent kinase activity, high selectivity, and superior oral pharmacokinetic profiles.