The kinesin class of microtubule-associated motor proteins present attractive anti-cancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms, and explore the implications for future anticancer drug development against these targets.
A series of imidazo[1,2-
b
]pyridazin-8-amine kinase inhibitors were
discovered to allosterically inhibit the endoribonuclease function
of the dual kinase-endoribonuclease inositol-requiring enzyme 1α
(IRE1α), a key component of the unfolded protein response in
mammalian cells and a potential drug target in multiple human diseases.
Inhibitor optimization gave compounds with high kinome selectivity
that prevented endoplasmic reticulum stress-induced IRE1α oligomerization
and phosphorylation, and inhibited endoribonuclease activity in human
cells. X-ray crystallography showed the inhibitors to bind to a previously
unreported and unusually disordered conformation of the IRE1α
kinase domain that would be incompatible with back-to-back dimerization
of the IRE1α protein and activation of the endoribonuclease
function. These findings increase the repertoire of known IRE1α
protein conformations and can guide the discovery of highly selective
ligands for the IRE1α kinase site that allosterically inhibit
the endoribonuclease.
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