How would sunitinib prevent HPK1 from functioning when it doesn’t bind directly to its active site?

Expert Solution

Sunitinib is a small molecule. It is a tyrosine kinase inhibitor. It inhibits HPK 1 which is also known as MAP4K 1 (Mitogen activated kinase kinase kinase kinase 1)

It inhibits several tyrosine kinases along with HPK 1 like VEGFR (Vascular endothelial growth factor) and PDGF (platelet derived growth factor) and thereby, reduce tumorigenesis and angiogenesis both.

We know that kinases activate downstream signaling by phosphorylating several target proteins and trigger a cascade. During these phosphorylation reactions ATP server as Phosphate group donor. Sunitinib mimicks ATP. Therefore, sunitinib competes with ATP for ATP binding site not for active site of HPK 1. Sunitinib has much higher affinity for the ATP binding pocket of the enzyme than ATP. When sunitinib will bind in place of ATP then the phosphate group donor (ATP) will not be available for subsequent substrate phosphorylation and hence,. downstream signaling cascade will be stopped. Therefore, sunitinib is a competitive inhibitor of ATP.

Sunitinib inhibits several kinases simultaneously because it is not specific for active site of any particular kinase but it competes with ATP, which is common phosphate group donor for almost all the kinases. This is also a reason for it's significant side effects and cardiotoxicity in chemotherapy receiving patients

gladiator answered 2 years ago

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