SCHEDULED MAINTENANCE:
Introduction to the themed collection on kinases
Hayley Binch, David E. Heppner, Meizhong Jin and Philip Jones introduce the RSC Medicinal Chemistry themed collection on kinases.
Leveraging artificial intelligence and machine learning in kinase inhibitor development: advances, challenges, and future prospects
This review highlights the integration of artificial intelligence (AI) and machine learning (ML) in the discovery of kinase inhibitors, showcasing recent advances, challenges, and the transformative potential of AI in precision drug design.
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.
Allosteric targeting of RIPK1: discovery of novel inhibitors via parallel virtual screening and structure-guided optimization
Parallel virtual screening and structure-guided optimization enable discovery of novel allosteric RIPK1 inhibitors.
Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader
Herein we highlight the discovery of a pan-mutant, orally bioavailable RET degrader with activity against intracranial tumors.
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.
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.
Research Article
A twist in the tale: shifting from covalent targeting of a tyrosine in JAK3 to a lysine in MK2
A fluorosulfate inhibitor designed for tyrosine unexpectedly formed a covalent bond with the “catalytic” lysine in MK2, revealing an unusual binding mode and highlighting new opportunities for non-cysteine covalent targeting in kinases.
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.
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.