Tyrosine Kinase inhibitors

1. Tyrosine Kinase inhibitors Presented BY : Group 5, PharmD. Supervised by : Dr. Nashaat.

2. Imatinib resistance • Resistance to imatinib is still a problem ,mainly in patients in • the accelerated Or blast crisis phases of the disease. • Resulting in : relapse or no progression (persistence). Imatinib resistance divided into the broad categories of primary and secondary resistance: 1-Primary resistance to imatinib, defined as an inability to achieve landmark response, is comprised of the 2% of patients who fail to achieve hematologic response and 8-13% who fail to achieve major or complete cytogenetic response using early chronic phase CML treated with imatinib at diagnosis as a benchmark. 2-Patients with secondary resistance—those who achieve but subsequently lose relevant response—is most straightforward for overt relapse such as loss of cytogenetic or hematologic response and progression from chronic to advanced-stage disease.

3. Imatinib resistance Mechanisms of Imatinib resistance: • Over-expression of BCR/ABL & BCR/ABL point mutations in • imtinib resistant leukemia: • the relapse is characterized by reactivation of BCR/ABL • kinase activity. 2. c-Kit & PDGFRa point mutations in GIST: an “enzymatic site” activating mutation which affects that catalytic portion of the KIT receptor kinase is associated with resistant to imatinib.

4. Imatinib resistance Mechanism of Imatinib resistance: 3. P-glycoprotein up regulation: i.e. over expression of multidrug resistance P-gp (efflux pump). 4. Alpha acid glycoprotein binding of imatinib: the plasma protein alpha 1 acid glycoprotein (AGP) has been proposed to bind to imatinib & prevent imatinib from reaching its target. Strategies to overcome imatinib resistance: 1- Combination therapy with imatinib: to improve response includes; the standard chemotherapeutic agents : cytosine arabinoside, daunorubicin, interferon alpha. 2- Modulation of imatinib dosing: by administration of higher (than conventional) doses of imatinib. 3- Second line therapy: Nilotinib, Dasatinib.

5. Nilotinib MOA • It is a selective BCR/ABL tyrosine kinase inhibitor, • also it inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs).

6. Dasatinib MOA • It binds to multiple conformations • of the ABL kinase, • dasatinib inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-B. By targeting these kinases, dasatinib inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ALL and allows normal red cell, white cell, and blood platelet production to resume.