3rd Generation Drugs currently being researched.....hope for the future!!!

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3rd Generation Inhibitors in Development-AP24534, VX-680 (MK-0457),

PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113

Curr Top Med Chem. 2008 ;8 (10):905-21 18673174 (P,S,G,E,

Inhibitors of ABL and the ABL-T315I Mutation.

Glenn Noronha, Jianguo Cao, Chun P Chow, Elena Dneprovskaia,

M Fine, Hood, Xinshan Kang, Boris Klebansky, Dan Lohse, Chi

Ching Mak, Andre McPherson, Moorthy S S Palanki, Ved P Pathak,

Renick, Soll, Binqi Zeng

TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA.

noronha@...

Chronic myelogenous leukemia (CML) is a hematological stem cell

disorder caused by increased and unregulated growth of myeloid cells

in the bone marrow, and the accumulation of excessive white blood

cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine

kinase involved in cell growth and proliferation and is usually under

tight control. However, 95% of CML patients have the ABL gene from

chromosome 9 fused with the breakpoint cluster (BCR) gene from

chromosome 22, resulting in a short chromosome known as the

Philadelphia chromosome. This Philadelphia chromosome is responsible

for the production of BCR-ABL, a constitutively active tyrosine

kinase that causes uncontrolled cellular proliferation. An ABL

inhibitor, imatinib, was approved by the FDA for the treatment of

CML, and is currently used as first line therapy. However, a high

percentage of clinical relapse has been observed due to long term

treatment with imatinib. A majority of these relapsed patients have

several point mutations at and around the ATP binding pocket of the

ABL kinase domain in BCR-ABL. In order to address the resistance of

mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as

dasatinib, and nilotinib were developed. These compounds were

approved for the treatment of CML patients who are resistant to

imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd)

generation inhibitors with the exception of the T315I mutant. Several

3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-

739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being

developed to target the T315I mutation. The early results from these

compounds are encouraging and it is anticipated that physicians will

have additional drugs at their disposal for the treatment of patients

with the mutated BCR-ABL-T315I. The success of these inhibitors has

greater implication not only in CML, but also in other diseases

driven by kinases where the mutated gatekeeper residue plays a major

role.

Thanks for reading,

Belfez