Targeting the T315I mutation in CML

[Guest guest]

Targeting T315I

Here is a synopsis of Burleigh (of SGX Pharmaceuticals) presentation at

last Tuesday’s symposium on IM Resistance, which I mentioned in an earlier

post. The subject was this company’s search for compounds that zap CML cells

containing the villainous mutant, T315I, but also wild type (unmutated) bcr/abl

containing cells.

Let me say first that the tools and techniques for drug discovery which

Burleigh discussed are nothing short of dazzling, orders of magnitude superior

in sophistication and speed to what was available just a few years back. Whereas

it took about 4 years of work to determine the exact structure of the bcr/abl

oncoprotein, these folk are able to characterize similar kinases (and their

mutant forms) in weeks or months – and design a range of potential drugs to

block them in an equivalently short time.

In fact, because they can do it so fast, Burleigh’s group is working

simultaneously all the resistant mutations in Deininger’s libarary of

bcr/abl kinase domain mutants, but since the T315I mutant causes the greatest

mischief, they’re focusing on this one particularly.

They have come up with several potential drugs, at least a couple of which show

similar potency as AMN to wild-type BA (bcr/abl), as well as substantial

activity against IM, DS or AMN-resistant T315I. In fact, their most promising

compound targets all the known kinase domain mutations except E255b. Since this

mutation occurs at a very low rate - less then 2% - this should not be of much

concern.

In order to bring these compounds quickly to trial, they use a very clever

method for assessing how toxic each is likely to be by testing against all the

kinases in the human “kinome†(the library of all 518 known normal human

kinases – see www.sciencemag.org/cgi/data/298/5600/1912/DC2/1 for a lovely

picture of the “evolutionary tree†of these kinases), and seeing which ones

it inhibits. Their favorite candidate inhibits 16 of the 518 known kinases, but

as this less than is seen with the existing CML drugs, they are quite confident

that the toxicity of theirs will be minimal. Interestingly, none of their

compounds target C-Kit or PDGFR. At least one of them targets FLT3, however,

which makes it a potential candidate drug for treating AML.

SGX Pharmaceuticals is “building in all the drug-like properties they needâ€

to move these compounds toward trial. Their goal is to submit their IND

(investigational new drug) application by the end of 2006, starting with

patients who are resistant or intolerant of the others three STIs. This might

seem long if you have a T315I mutation, but it’s warp speed compared to what

would have been possible only a few years ago.

Assuming they can turn these compounds into effective drugs which pass the FDA

gauntlet, SGX’s hope is that they will be used in combination with one of the

existing STI’s as first-line therapy, to prevent and/or treat resistance.

Burleigh compared this strategy to that of multi-drug anti-retroviral therapy

for HIV/AIDS.

Naturally SGX is hoping eventually the use of their drug for other indications

besides CML as IM is used for GIST, hypereosinophilia syndrome, etc. They are

actively seeking collaboration with other partners for further development.

Cheers,

R