George, thanks as usual, this is indeed the key to whether ENMD-2076 can be "competitive" (heh, heh). It must compete for the ATP (or allosteric) binding sites in order to compete with Gleevec and the other kinase enzyme inhibitors.
Look at the one quote in one of the papers you referenced:
"However, we have to be aware of the fact that in the protein kinase area, it will be very much unlikely to find a unique compound that specifically inhibits a selected single protein kinase, leaving the other more than 500 protein kinases unaffected. On the other hand, with sufficient structural biology information about the binding mode and possible interactive sites and related pharmacophore modeling, it may be possible to develop protein kinase inhibitors which can have a ‘‘reasonable side effect profile.’’
This is why these drugs affect so many different cell division switches at the same time. It's like the mood altering benzodiazepine drugs, valium xanax and klonopin - they all fit CNS nerve cells more than peripheral nerve cells and some CNS nerve cells more than others (some of these drugs may do better for turning down cells for epilepsy or simple twitches or anxiety) and the SSRI drugs for depression are "selective" for certain nerves.
I haven't yet read up much on the allosteric site binding requirements, so I don't know if the structure of ATP "fits" (heh, heh) this site or not yet, but I don't think that matters as much. Though there might be one drug around that inhibits both of these sites.
But I think it's clear now that the nitrogen rings in ENMD-2076 mimic the nitrogen rings in ATP in order to gain access to the ATP binding site and thus cause inhibition. Covalent binding to the site is known and could be introduced by one of the ENMD-2076 analogs that has an electrophilic chemical moiety (look for C-Cl or C=C-CO groups in the analogs in the table as well as other groups). The group would have to be in a position such that in the enzyme cleft it would be opposed by a cysteine amino acid sulfur atom. All this is well known.
Early results should be good, since ENMD-2076 is known to be rationally designed and has already provided the expected pre-Phase 2 results. What needs to be found out is if (a) ENMD-2076 can overcome the problems of kinase enzyme mutations to maintain its inhibition of ATP-mediated signaling of cell division and blood vessel formation; and (b) if patients can do well for months/years/lifetime. You can see on www.clinicaltrial.gov that Gleevec is being tried in drug combinations now. This would probably be where ENMD-2076 is headed next if it makes it thru P2.
I still think that ENMD-2076 and its analogs should have some value to someone because there are so many cancers, so many different genetic patient enzymes, so many different combinations of drugs and analogs, and this is still a fairly new field of cancer drugs starting its genesis after the human genome mapping in the mid 1980s. There is cash on hand, royalties, hundreds of analogs and other intellectual value to the company. The market cap now must be close to $30 Million, which sounds almost worthless for what the potential still is.
Off to breakfast out today. Paul
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