Re: PI3K inhibitors

[Guest guest]

At 04:19 PM 4/13/2011, cllcanada wrote:

>What is the difference between a reversible (LY294002) and

>irreversible (Wortmannin) PI3K inhibitors?

Generally speaking with regard to reversible vs.

irreversible inhibitors: PI3K is an enzyme (a class of

proteins) and enzymes catalyze chemical reactions which

alter the chemical structures of molecules. The usual

chemical difference between reversible and irreversible

inhibitors of enzymes is that reversible inhibitors form

weaker ( " non-covalent " ) interactions with enzymes than do

irreversible inhibitors of enzymes, which usually will form

a ( " covalent " ) chemical bond between the inhibitor and the

enzyme, bonds which usually cannot be easily broken again

without another enzymatic reaction.

Probably the most common covalent modification of proteins

(including enzymes) that occurs in nature is the addition

and removal of phosphate groups. Depending a variety of

biochemical factors, an addition of a covalent phosphate

group can either increase or decrease a given function of a

protein.

For example, " protein kinases " (like PI3K), which catalyze

the covalent addition of phosphate groups onto protein

molecules, are often themselves regulated by other kinases

adding covalent phosphate groups onto those kinases. The

addition of the phosphate groups can either increase or

decrease the protein's normal functions, and the covalently-

bound phosphate groups can be removed by other enzymes

( " phosphatases " ), returning the protein's functions back to

what it was before the phosphate was added.

Off-hand, I do not know the specific mechanism by which

LY294002 reversibly inhibits PI3K and by which Wortmannin

irreversibly inhibits PI3K, but I'm sure that information is

in published literature.

Al Janski

[Guest guest]

Thanks, Al. I may have followed much of what you wrote. : )

I think I see how the chemical binding mechanisms can

influence reversibility, but assuming the target protein is

a ongoing product of cell machinery ... leading to

additional proteins, wouldn't this lead to reversibility in

any case - the need to continously treat? (like a protective

skin ointment that you have to reapply as new skin cells

emerge)

Karl

[Guest guest]

At 08:46 AM 4/14/2011, Karl wrote:

> I think I see how the chemical binding mechanisms can

influence reversibility, but assuming the target protein is

a ongoing product of cell machinery ... leading to

additional proteins, wouldn't this lead to reversibility in

any case - the need to continuously treat? (like a protective

skin ointment that you have to reapply as new skin cells

emerge)

________________end quote________

It is the process of proliferation of new CLL cells, not the

process of proliferation of new PI3K molecules within a

given CLL cell, that is most important.

If PI3K inhibitors (reversible or irreversible) decrease the

activities, as expected, of the many PI3K protein molecules

in each individual CLL cell, then, because those PI3K

activities support cell survival, those CLL cells will be

less likely to survive, including (as has been reported by

Calistoga for CAL-101) less likely to survive within the

microenvironments of the proliferation centers (nodes,

spleen, marrow, etc.) in which CLL cells divide and produce

new CLL cells, containing new PI3K protein molecules.

Using targeted therapeutic molecules to selectively inhibit

specific proteins (such as enzymes like PI3K, or regulatory

proteins like p53) can never be 100% effective in inhibiting

all of the molecules of a specific protein within a given

cell. However, for all biochemical pathways, it is not

necessary to inhibit 100% of the molecules of a key protein

(like PI3K) of a given pathway to alter the fate of a given

cell, because it is only necessary to slow the production of

a given pathway enough, relative to competing pathways

within that cell, to change the fate of that given cell.

Even if it were biochemically feasible to achieve 100%

inhibition of the functions of all the molecules of a given

targeted protein, that would not be a desirable objective

for treatment of cancer cells, because almost always the

process of administering these targeted therapies will

expose some normal cells to the therapies and the targeted

biochemical pathways within those cancer cells also exist

(and are necessary for the proper functioning) of some

important normal cells. The balance between sufficient

inhibition of cancer cell pathways vs. minimal inhibition

normal cell pathways is at the core of the balance between

efficacy vs. toxicity of such targeted therapeutics.

Al Janski

[Guest guest]

Makes sense, Al. Thanks for the explanation. ~ Karl

> It is the process of proliferation of new CLL cells, not the

> process of proliferation of new PI3K molecules within a

> given CLL cell, that is most important.