Title: ARIAD Presents New Preclinical Data on Ponatinib and AP26113
Date(s): 2-Apr-2012 9:00 AM
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Both Tyrosine Kinase Inhibitors Overcome Drug Resistance Due to
Gatekeeper Mutations Of Multiple Oncogenic Targets
CAMBRIDGE, Mass. & CHICAGO--(BUSINESS WIRE)--Apr. 2, 2012--
ARIAD
Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the
presentation of new preclinical data on its investigational pan-BCR-ABL
inhibitor, ponatinib,
and its investigational dual EGFR-ALK inhibitor, AP26113, at the
American Association for Cancer Research Annual Meeting in Chicago. Both
drug candidates, discovered using ARIAD s structure-based drug design
platform, are potent inhibitors of multiple gatekeeper mutations that
have been shown to confer clinical resistance to other targeted cancer
medicines.
The first study, Ponatinib, a potent pan-BCR-ABL inhibitor, retains
activity against gatekeeper mutants of FLT3, RET, KIT, PDGFR and FGFR1,
was presented yesterday and shows that ponatinib overcomes resistant
gatekeeper mutations well beyond BCR-ABL -- the drug s target in chronic
myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic
leukemia (Ph+ ALL) -- in other clinically relevant tyrosine kinase
targets.
The preclinical research conducted by ARIAD scientists assessed the
activity of ponatinib using cell lines expressing activated forms of
FLT3, RET, KIT, PDGFR and FGFR1, each a kinase target associated with a
specific tumor type. Ponatinib potently inhibited the activity of these
kinases and maintained potent activity against gatekeeper variants that
have been shown to cause resistance to other tyrosine kinase inhibitors
in acute myeloid leukemia, medullary thyroid cancer, gastrointestinal
stromal tumor (GIST) and rare forms of leukemia driven by these tyrosine
kinases.
Ponatinib was designed to block the abnormal tyrosine kinase, BCR-ABL,
which drives CML and Ph+ALL, said Timothy
P. Clackson, Ph.D., president of research and development and chief
scientific officer of ARIAD. The structural design feature that allows
ponatinib to evade the BCR-ABL T315I gatekeeper mutation also enables
the molecule to overcome analogous mutations in its other kinase
targets. We are actively working with academic collaborators to set up
clinical trials aimed at determining the potential role of ponatinib in
these additional forms of drug-resistant cancer.
A second abstract, AP26113 is a dual ALK/EGFR inhibitor:
Characterization against EGFR T790M in cell and mouse models of NSCLC,
will be presented today and describes the activity of AP26113,
a dual inhibitor of EGFR and ALK, to overcome gatekeeper mutations of
these targets. This preclinical research further confirms that AP26113
is a potent, reversible inhibitor of the T790M gatekeeper mutation of
epidermal growth factor receptor (EGFR). Activated EGFR occurs in
approximately 250,000 lung cancer patients worldwide, and the single
T790M mutation accounts for over 50 percent of resistance to tyrosine
kinase inhibitors in these patients who have limited treatment options
available.
This poster also presents, for the first time, preclinical data
demonstrating that AP26113 potently inhibits non-small cell lung cancer
(NSCLC) cell lines that express an activating translocation of the ROS1
tyrosine kinase. Such ROS1 mutations have recently been identified as a
feature of approximately two percent of all NSCLC, representing another
area for further investigation of AP26113 in NSCLC patients in need of
better therapeutic choices.
