Hello,

I assume here that your inhibitors will target clonal diseases. If the idea is to go into clinics I would definitely pick 1. Multitarget often means toxicity. The most important factors to consider are that your target should be critical for cancer cell survival and should be non-critical for normal cells. Paradigm is Imatinib.

Hi Rocco, 

Thank you for your reply. Imatinib has found to be active against other kinases rather Bcr-Abl only. Dasatinib is showing promising result even with its high non-selectivity.  So, thoughts are shifting. I am having just some speculation from articles but not really the proper evidence that could support one of these ideas completely. 

Best 

dear Khan Md Taufiqul Arif

To design a kinase inhibitor which criterion should we follow..

1. Solitary target with number of compounds

- as a single target cannot be ....single. Pathway and interconnected chains of the intercellular connections will provide additional target inhibition.

One inhibitor cannot inhibit all of the known growth factors, and given the huge number of mutations in any tumorogenesis, it turns out that multi-target with single compound is a complication of the way.

And then there are the clusters of differentiation, which further complicate the task in the pathway multi-target with single compound....

I think so

Regards

Dear Petrov, 

Thank you for he reply. 

what are you suggesting? How about combination strategy: combine few selective inhibitors together ?

I've been doing this for several years, having extensive clinical practice.

Building a treatment strategy, taking the data on the toxic and side effects, patients are taking several selective inhibitors. Braking is the way to build , knowing that initially they begin - Ras-RAF-MEK-PI3K, etc .Example inhibitors of the Raf-MEK (vemurafenib + trametinib) in BRAF mutant tumors.

The problem is that today there are a huge number of inhibitors that hindered the giants of the Pharma industry. It is unprofitable to dump prices a number of high quality (pan-inhibitors that inhibit mutant forms and wild type).

Clinical research is a marketing process, acquisitions, mergers, but-monopoly.

(one example is https://en.wikipedia.org/wiki/Medivation )

Clinical studies aimed at proving effectiveness of treatment, but not treatment

Treatment involved doctors prescribing drugs with proven efficacy. But each doctor's Protocol, which he is obliged to apply. There is no Protocol,- no treatment. A Protocol is a clinical research... a vicious circle

Generally it is difficult to...)))))

I have long wanted to start a series of lectures on the clinical practice of combining a strategy of gradual closure of the cellular pathways of tumor growth in clinical practice... So please... share what you can.

Dear Petrov, 

Thank you so much for the insightful response. As a beginner I feel privileged to deal with  such issues and truly a bit puzzled watching versatility between in vitro and in vivo data.  So, scratching the surface to gain some basic knowledge prior to develop any scheme. Hope more will be discussed here and obliged thereby. 

Targeting multiple kinase of same disease was really a good approach but it will increase toxicity as Dr. Piazza said. Still  i believed in targeted therapy with effective  treatment of disease and less toxicity. For this purpose multi target is useful but at initial point we all need to find target for work. This is truely puzzled question and answer is buried under the experimental facts.

Go ahead, All the best

Well, i think 'Polypharmacology' is the answer to your question. A promiscuous inhibitor effecting many targets is surely undesirable. But through polypharmacology we design a molecule which inhibits two or three targets. 

I don't know your specific area of research. But if you do CADD or MedChem, then: we design a single molecule, where part of it is significant in binding to the pocket of one taget and the other part of the molecule to the other target. However, the whole molecule should fit in the binding site of both targets.

In case of kinase inhibitors, this is possible because the catalytic domain in quite conserved.