How does ARIAD's Ponatinib (Iclusig) Work

Mechanism of Action Series: Ponatinib

Ariad Pharmaceuticals' leukemia drug ponatinib has been in the news lately for major toxicity fears that can potentially derail its further clinical development. While these issues will be sorted out in coming months, it's a good time to review how does this drug work.

Ponatinib is a pan-inhibitor of native and T315I mutant forms of BCR-ABL kinase.

HiJAKing the JAKs in Myeloproliferative Disorders

Myeloproliferative neoplasms (MPNs) are characterized by uncontrolled proliferation of differentiated myeloid cells in the bone marrow, and have an underlying clonal genetic change.  They often evolve into acute myelogenous leukemia (AML).  MPNs with chromosomal translocation t(9;22) BCR-ABL, also called Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), have a very good prognosis.  Imatinib (Gleevec; Novartis) is a very effective inhibitor of BCR-ABL kinase.  On the other hand, Ph-negative MPNs, until recently had lacked targeted approaches.  This changed in 2005 with the discovery of a dominant gain-of-function somatic mutation in Janus Kinase-2 (JAK2) of a significant proportion of MPNs, wherein guanine-to-thymidine substitution results in a valine-to-phenylalanine change at position 617.