Re: Drug shows promise in leukemia treatment

[Guest guest]

PD166326 is not such a new drug. Rowbotham first brought it to our

attention in 2002.

It has taken over 3 years for someone to publish the characterization of

this drug in animals.

Here is 's email from 2002. He was a superb researcher and we miss him.

His post follows.

Zavie

Also, the report by Sausville in 2003 is really worth reading.

http://clincancerres.aacrjournals.org/cgi/content/full/9/4/1233

Rowbotham

Subject: The extraordinary PDs again!

I have written for a long time about the various Parke (now part of

Pfizer) inhibitors - the PD compounds, and talked to Pfizer directly about

these. They are very good indeed if the reports are to be taken literally,

but up to now, out of reach of patients. One of the problems Pfizer

mentioned was solubility (apparently necessary for these compounds to be

delivered as oral drugs), but that is being overcome. The other problem,

much harder to beat, is that there is no money to be made from producing

these drugs for CML patients. Nevertheless, it is encouraging that work goes

on with these compounds, and as one AACR paper suggests " this structural

class of compounds may serve as a prototype for the next generation of

anti-CML therapeutics. " Not only are they more potent than STI (Gleevec),

but some of them can also apparently deal with resistant cells. Perhaps

something may yet come from this research that is valuable for CML patients

in the not-too-distant future.

I have attached some bits and pieces from several abstracts below. To find

these in their original form, go to www.aacr.org and look at the 2002

meeting abstracts.

Abstract #4198 (written by an MKSCC team)

[Novel therapies are needed to suppress or overcome resistance to inhibitors

of Abl tyrosine kinase. We have hypothesized that combined inhibition of

BCR-Abl and downstream signaling pathways may prove to be a more effective

form of therapy. Since src kinases function downstream of BCR-Abl and are

structurally related to the Abl tyrosine kinase, we have sought to identify

small molecule tyrosine kinase inhibitors that inhibit both signaling steps.

Screening a family of src-selective inhibitors, we have identified a

pyrido[2,3-d]pyrimidine compound that potently inhibits src and Abl kinases

in vitro and in vivo. The molar potency of this compound is 100 times higher

than STI-571 against the BCR-Abl positive K562 cells....

....The potency and cellular specificity of this dual inhibitor suggest that

this structural class of compounds may serve as a prototype for the next

generation of anti-CML therapeutics.]

Abstract #4199 (MSKCC)

[However, the utility of PD173955 is debased by its poor solubility....

....We report here the synthesis and in vitro and in vivo evaluation of a

focused library of inhibitors based on PD173955, one of which, PD166326, has

already been shown to have improved solubility and a 3 to 4-fold increase in

potency (in vitro IC50 of 0.13-0.5 nM) over PD173955.]

[ ] Drug shows promise in leukemia treatment

Hello All,

Another new drug on the market?

Drug shows promise in leukemia treatment

<http://images.washtimes.com/images/clear.gif>

<http://images.washtimes.com/images/twt-grey2.gif>

Dallas, TX, May. 2 (UPI) -- An experimental drug 100 times more potent than

any now available shows promise in treating one kind of leukemia,

researchers said Monday.

<http://z1.adserver.com/w/cp.x;rid=319;tid=20;ev=2;dt=3;ac=42;c=431;>

<http://z1.adserver.com/w/cp.x;rid=319;tid=20;ev=2;ac=42;mid=4891>

The University of Texas Southwestern Medical Center study showed the

experimental drug might be effective against human chronic myelogenous

leukemia, which strikes about 5,000 Americans a year and has proved

resistant to treatment.

" This novel anti-leukemia drug that we have been working on shows

considerable promise for going into the clinic, " said Dr. Ilaria Jr.,

an associate professor and senior author of the study that will appear in an

upcoming issue of Blood. It has been published online.

The experimental drug, called PD166326, was tested on mice with a similar

form of leukemia. The tests showed it was nearly 100 times more potent than

imatinib, which targets a mutated enzyme produced by patients with the

specific form of leukemia. Up to 20 percent of patients taking imatinib

develop resistance to the drug.

" Our study represents the first published characterization of this novel

anti-leukemia drug in animals, " Dr. Ilaria said.

[Guest guest]

-Thanks for this Zavie,

It looks like the researches have continued working on it in spite of

the great success of Gleevec.

I've read and heard a lot about , it's unfortunate that some

many good people have left our information group. I have heard that

he is well and enjoying life, although sadly without his wife, out in

. He contributed so much, it is nice to see some of the

projects he spoke to us about being brought up again.

Cheers,

Cheryl-Anne

-- In , " Zavie " <zmiller@s...> wrote:

> PD166326 is not such a new drug. Rowbotham first brought it

to our

> attention in 2002.

>

> It has taken over 3 years for someone to publish the

characterization of

> this drug in animals.

>

> Here is 's email from 2002. He was a superb researcher and we

miss him.

> His post follows.

>

> Zavie

>

> Also, the report by Sausville in 2003 is really worth reading.

> http://clincancerres.aacrjournals.org/cgi/content/full/9/4/1233

>

>

> Rowbotham

> Subject: The extraordinary PDs again!

>

> I have written for a long time about the various Parke (now

part of

> Pfizer) inhibitors - the PD compounds, and talked to Pfizer

directly about

> these. They are very good indeed if the reports are to be taken

literally,

> but up to now, out of reach of patients. One of the problems Pfizer

> mentioned was solubility (apparently necessary for these compounds

to be

> delivered as oral drugs), but that is being overcome. The other

problem,

> much harder to beat, is that there is no money to be made from

producing

> these drugs for CML patients. Nevertheless, it is encouraging that

work goes

> on with these compounds, and as one AACR paper suggests " this

structural

> class of compounds may serve as a prototype for the next generation

of

> anti-CML therapeutics. " Not only are they more potent than STI

(Gleevec),

> but some of them can also apparently deal with resistant cells.

Perhaps

> something may yet come from this research that is valuable for CML

patients

> in the not-too-distant future.

>

> I have attached some bits and pieces from several abstracts below.

To find

> these in their original form, go to www.aacr.org and look at the

2002

> meeting abstracts.

>

>

> Abstract #4198 (written by an MKSCC team)

>

> [Novel therapies are needed to suppress or overcome resistance to

inhibitors

> of Abl tyrosine kinase. We have hypothesized that combined

inhibition of

> BCR-Abl and downstream signaling pathways may prove to be a more

effective

> form of therapy. Since src kinases function downstream of BCR-Abl

and are

> structurally related to the Abl tyrosine kinase, we have sought to

identify

> small molecule tyrosine kinase inhibitors that inhibit both

signaling steps.

> Screening a family of src-selective inhibitors, we have identified a

> pyrido[2,3-d]pyrimidine compound that potently inhibits src and Abl

kinases

> in vitro and in vivo. The molar potency of this compound is 100

times higher

> than STI-571 against the BCR-Abl positive K562 cells....

>

> ...The potency and cellular specificity of this dual inhibitor

suggest that

> this structural class of compounds may serve as a prototype for the

next

> generation of anti-CML therapeutics.]

>

> Abstract #4199 (MSKCC)

>

> [However, the utility of PD173955 is debased by its poor

solubility....

>

> ...We report here the synthesis and in vitro and in vivo evaluation

of a

> focused library of inhibitors based on PD173955, one of which,

PD166326, has

> already been shown to have improved solubility and a 3 to 4-fold

increase in

> potency (in vitro IC50 of 0.13-0.5 nM) over PD173955.]

>

>

>

> [ ] Drug shows promise in leukemia treatment

>

>

> Hello All,

>

> Another new drug on the market?

>

> Drug shows promise in leukemia treatment

> <http://images.washtimes.com/images/clear.gif>

> <http://images.washtimes.com/images/twt-grey2.gif>

>

> Dallas, TX, May. 2 (UPI) -- An experimental drug 100 times more

potent than

> any now available shows promise in treating one kind of leukemia,

> researchers said Monday.

>

>

<http://z1.adserver.com/w/cp.x;rid=319;tid=20;ev=2;dt=3;ac=42;c=431;>

> <http://z1.adserver.com/w/cp.x;rid=319;tid=20;ev=2;ac=42;mid=4891>

>

> The University of Texas Southwestern Medical Center study showed the

> experimental drug might be effective against human chronic

myelogenous

> leukemia, which strikes about 5,000 Americans a year and has proved

> resistant to treatment.

>

> " This novel anti-leukemia drug that we have been working on shows

> considerable promise for going into the clinic, " said Dr.

Ilaria Jr.,

> an associate professor and senior author of the study that will

appear in an

> upcoming issue of Blood. It has been published online.

>

> The experimental drug, called PD166326, was tested on mice with a

similar

> form of leukemia. The tests showed it was nearly 100 times more

potent than

> imatinib, which targets a mutated enzyme produced by patients with

the

> specific form of leukemia. Up to 20 percent of patients taking

imatinib

> develop resistance to the drug.

>

> " Our study represents the first published characterization of this

novel

> anti-leukemia drug in animals, " Dr. Ilaria said.

>

>

>

>

[Guest guest]

Hey Cheryl,

Thanks for posting this. There was an abstract about PD166326 at ASH 2003,

and it's interesting to see that work is still being done on it. What's not

clear from the abstract is whether it's effective against the T315I mutation

(which is resistant to IM, AMN 107 and BMS-354825).

The number of new agents and combination therapies being studied is also

becoming something of a problem, I understand: it's getting hard to recruit

enough patients to each of the studies. It will be interesting to see how

this plays out. I note that no mention is made here of upcoming trials for

PD166326....

Cheers,

R

PS - I met Ruth Marcon in town PA today - what a great lady! She

didn't know about this list so I told her. I gather she hasn't been

following any of the lists lately, but she wondered where a number of us had

gone.

> Date: Mon, 2 May 2005 19:44:24 -0400

> From: " Cheryl-Anne Simoneau " <cheryl.simoneau@...>

> Subject:

>

> Here's the abstract - Full article to follow....

>

> Blood, 15 May 2005, Vol. 105, No. 10, pp. 3995-4003.

> Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI

> 10.1182/blood-2004-09-3534.

>

> Submitted September 14, 2004

> Accepted January 9, 2005

>

> PD166326, a novel tyrosine kinase inhibitor, has greater anti-leukemic

> activity than imatinib in a murine model of chronic myeloid leukemia

>

> C Wolff, Darren R Veach, P Tong, G Bornmann, Bayard

> son, and L Ilaria*

>

> Hamon Center for Therapeutic Oncology Research, University of Texas

> Southwestern Medical Center, Dallas, TX, USA Molecular Pharmacology and

> Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

> Division of Hematology/Oncology, Department of Medicine, University of Texas

> Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Therapeutic

> Oncology Research, University of Texas Southwestern Medical Center, Dallas,

> TX, USA

>

> Imatinib mesylate is highly effective in newly diagnosed chronic myeloid

> leukemia (CML), but BCR/ABL-positive progenitors persist in most

> imatinib-treated CML patients, indicating the need for novel therapeutic

> approaches. In this study, we have used the murine CML-like

> myeloproliferative disorder as a platform to characterize the

> pharmacokinetic, signal transduction, and anti-leukemic properties of

> PD166326, one of the most potent members of the pyridopyrimidine class of

> protein tyrosine kinase inhibitors. In mice with the CML-like disease,

> PD166326 rapidly inhibited Bcr/Abl kinase activity after a single oral dose,

> and demonstrated marked anti-leukemic activity in vivo. Seventy percent of

> PD166326-treated mice achieved a WBC less than 20 000/µL at necropsy,

> compared with only 8% of imatinib-treated animals. Further, two-thirds of

> PD166326-treated animals had complete resolution of splenomegaly, compared

> to none of the imatinib-treated animals. Consistent with its more potent

> anti-leukemic effect in vivo, PD166326 was also superior to imatinib in

> inhibiting the constitutive tyrosine phosphorylation of numerous leukemia

> cell proteins, including the src family member Lyn. PD166326 also prolonged

> the survival of mice with imatinib-resistant CML induced by the Bcr/Abl

> mutants P210/H396P and P210/M351T. Altogether, these findings demonstrate

> the potential of more potent Bcr/Abl inhibitors to provide more effective

> anti-leukemic activity. Clinical development of PD166326 or a related

> analogue may lead to more effective drugs for the treatment of de novo and

> imatinib-resistant CML.

[Guest guest]

Hey

Thanks for your insight on this. I wonder if we would have ever

thought that we would see the day when there would be more new drugs

than there would be patients to trial them.

Ruth is a wonderful lady, I thought she knew about this place. I

will write to her.

Cheers,

Cheryl-Anne

> Hey Cheryl,

>

> Thanks for posting this. There was an abstract about PD166326 at

ASH 2003,

> and it's interesting to see that work is still being done on it.

What's not

> clear from the abstract is whether it's effective against the T315I

mutation

> (which is resistant to IM, AMN 107 and BMS-354825).

>

> The number of new agents and combination therapies being studied is

also

> becoming something of a problem, I understand: it's getting hard

to recruit

> enough patients to each of the studies. It will be interesting to

see how

> this plays out. I note that no mention is made here of upcoming

trials for

> PD166326....

>

> Cheers,

>

> R

>

> PS - I met Ruth Marcon in town PA today - what a great lady!

She

> didn't know about this list so I told her. I gather she hasn't been

> following any of the lists lately, but she wondered where a number

of us had

> gone.

>

>

>

> > Date: Mon, 2 May 2005 19:44:24 -0400

> > From: " Cheryl-Anne Simoneau " <cheryl.simoneau@m...>

> > Subject:

> >

> > Here's the abstract - Full article to follow....

> >

> > Blood, 15 May 2005, Vol. 105, No. 10, pp. 3995-4003.

> > Prepublished online as a Blood First Edition Paper on January 18,

2005; DOI

> > 10.1182/blood-2004-09-3534.

> >

> > Submitted September 14, 2004

> > Accepted January 9, 2005

> >

> > PD166326, a novel tyrosine kinase inhibitor, has greater anti-

leukemic

> > activity than imatinib in a murine model of chronic myeloid

leukemia

> >

> > C Wolff, Darren R Veach, P Tong, G

Bornmann, Bayard

> > son, and L Ilaria*

> >

> > Hamon Center for Therapeutic Oncology Research, University of

Texas

> > Southwestern Medical Center, Dallas, TX, USA Molecular

Pharmacology and

> > Chemistry Program, Memorial Sloan-Kettering Cancer Center, New

York, NY, USA

> > Division of Hematology/Oncology, Department of Medicine,

University of Texas

> > Southwestern Medical Center, Dallas, TX, USA; Hamon Center for

Therapeutic

> > Oncology Research, University of Texas Southwestern Medical

Center, Dallas,

> > TX, USA

> >

> > Imatinib mesylate is highly effective in newly diagnosed chronic

myeloid

> > leukemia (CML), but BCR/ABL-positive progenitors persist in most

> > imatinib-treated CML patients, indicating the need for novel

therapeutic

> > approaches. In this study, we have used the murine CML-like

> > myeloproliferative disorder as a platform to characterize the

> > pharmacokinetic, signal transduction, and anti-leukemic

properties of

> > PD166326, one of the most potent members of the pyridopyrimidine

class of

> > protein tyrosine kinase inhibitors. In mice with the CML-like

disease,

> > PD166326 rapidly inhibited Bcr/Abl kinase activity after a single

oral dose,

> > and demonstrated marked anti-leukemic activity in vivo. Seventy

percent of

> > PD166326-treated mice achieved a WBC less than 20 000/µL at

necropsy,

> > compared with only 8% of imatinib-treated animals. Further, two-

thirds of

> > PD166326-treated animals had complete resolution of splenomegaly,

compared

> > to none of the imatinib-treated animals. Consistent with its more

potent

> > anti-leukemic effect in vivo, PD166326 was also superior to

imatinib in

> > inhibiting the constitutive tyrosine phosphorylation of numerous

leukemia

> > cell proteins, including the src family member Lyn. PD166326 also

prolonged

> > the survival of mice with imatinib-resistant CML induced by the

Bcr/Abl

> > mutants P210/H396P and P210/M351T. Altogether, these findings

demonstrate

> > the potential of more potent Bcr/Abl inhibitors to provide more

effective

> > anti-leukemic activity. Clinical development of PD166326 or a

related

> > analogue may lead to more effective drugs for the treatment of de

novo and

> > imatinib-resistant CML.

[Guest guest]

<snip>

PS - I met Ruth Marcon in town PA today - what a great lady! She

didn't know about this list so I told her. I gather she hasn't been

following any of the lists lately, but she wondered where a number of us had

gone.

We met Ruth at the Fall Ball in Niagara Falls back in 2002. Had a ball.

Ruth is # 93 in the Zero Club

Zavie