Nilotinib: Difference between revisions

<StructureSection load='' size='350' side='right' scene='Nilotinib/Nilotinib/1' caption='Nilotinib, also known as Tasigna ([[3cs9]])'>

* Marketed By: Novartis

* Major Indication: Chronic Myelogenous [[Cancer|Leukemia]] (CML)

* Drug Class: Receptor Tyrosine Kinase (Especially, PDGFR, KIT &  BCR-Abl) Inhibitor

* Date of FDA Approval (Expiration): 2007 (2023)

* Expected Sales in Combination with [[Imatinib]]: $5 Billion

* Importance: It is a powerful second generation BCR-Abl inhibitor designed to work against [[Imatinib]] resistant CML. Recent studies have revealed that Nilotinib is more effective than Gleevec in treating blood [[cancer]], highlighting that Nilotinib might be considered the Gold standard CML treatment in a few years.<ref>PMID:1672137</ref>

Chronic Myelogenous [[Cancer|Leukemia]] (CML) results from a gene defect in a haematological stem cell, <scene name='Nilotinib/Bcr/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Nilotinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Nilotinib/Dfg/2'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Nilotinib/Gate/1'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Nilotinib/Gate/2'>Thr 315 shifts to allow binding of Nilotinib</scene>. In other kinases like B-Raf, p38 & KDR, position 315 is occupied by a larger residue that is not conducive to Nilotinib binding, giving Nilotinib its high specificity.<ref>PMID:17164530</ref> A number of point mutations within BCR-Abl result in [[Imatinib]] resistance. There are 33 well known Imatinib resistance conferring mutations at positions like 244, 250, 252, 253, 315, 317, 351, and 396. Nilotinib has shown effectiveness with nearly all Imatinib resistant versions of BCR-Abl, with the exception of the T315I mutant. <ref>PMID:16172030</ref> In BCR-Abl, <scene name='Nilotinib/Binding/2'>Nilotinib is bound</scene> by H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, along with hydrophobic interactions with residues His 361, Ile 293, Ala 380, Val 299, Met 290, Lys 271, & Ala 269, stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref><ref>PMID: 15710326</ref>