Nilotinib

spinqualitylabelsall models Nilotinib, also known as Tasigna (3cs9) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Better Known as: Tasigna Marketed By: Novartis Major Indication: Chronic Myelogenous 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. See Pharmaceutical Drugs for more information about other drugs and disorders Mechanism of Action Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, producing the kinase, BCR-Abl. 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 "DFG triad" is in the "out" conformation. A critically important residue, Thr 315, is known as the gatekeeper residue. In the inactive DFG out conformation, Thr 315 shifts to allow binding of Nilotinib. 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. 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. In BCR-Abl, Nilotinib is bound 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. To see morphs of the movement of key structural elements Click: DFG Movement, P-Loop Movement, & the Activation Loop Movement.

Pharmacokinetics

Tyrosine Kinase Inhibitor Leukemia Imatinib & KIT Inhibitors Imatinib Inhibitors BCR-Abl Inhibitor Parameter cancer (Sutent) Pharmaceutical Drugs (Nexavar) Leukemia (Tarceva) Imatinib (Iressa) Lapatinib (Tykerb) Imatinib (Gleevec) Nilotinib (Tasigna) Dasatinib (Sprycel) Tmax (hr) 8 8.3 2.0 5.4 4 3.7 3.0 1.0 Cmax (ng/ml) 24.6 460 69.6 130 115 2070 411 124 Bioavailability (%) Variable 29-49 99 59 Variable 98 30 20 Protein Binding (%) 95 99 93 90 99 95 98 96 T1/2 (hr) 83 29 9.4 26.9 9.6 26.6 16.0 3.3 AUC (ng/ml/hr) 1921 11040 20577 3850 1429 4760 10052 461 Dosage (mg) 50 50 150 250 100 400 200 200 Metabolism Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) For Pharmacokinetic Data References, see: References

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