Innovation Pharmaceuticals Inc (IPIX)

[KMBJN]

Glad to see you back posting interesting things again SLC.

Tumor spread, or metastasis, is a primary reason cancer is lethal.

I was talking last week to an inventor of a very promising anti-metastatic agent. There really are no drugs designed specifically to do this. I hope kevetrin will someday be proven to help kill the primary tumor, any metastases, and also prevent future mets.

The mechanism of action of the new drug is complex, but they think it may be a multi-kinase inhibitor that inhibits the HSP90-CDC37 co-chaperone complex. They found it by screening analogs of genistein for inhibition of cancer cell motility in vitro, then have been testing it in mice - safe at maximum feasible dose given, with a startup trying to get an IND and into clinical trials.

HSPs 90 and 70 and HIP and HOP and CDC37 and P23 and on and on it goes - so many protein interactions and HSP90 is in the center of it all. It's possible the new antimetastatic drug may work by inhibiting MMP-2 outside of cells (these enzymes cut through the external cellular matrix to allow movement of cells), but they haven't really looked at this type of thing:

https://www.ncbi.nlm.nih.gov/pubmed/21533148

There are many HSP90 inhibitors in trials, but so far none have proven out. There are many binding sites on HSP90.

https://www.ncbi.nlm.nih.gov/pubmed/27013225
https://www.ncbi.nlm.nih.gov/pubmed/19414312

I think HSP70 inhibitors are just starting to be developed.

HSP90 and HSP70 also stabilize wild-type p53:

https://www.ncbi.nlm.nih.gov/pubmed/19749793

and the co-chaperone complex interacts with mutant p53:

https://www.ncbi.nlm.nih.gov/pubmed/11707401

I recall that kevetrin may somehow affect the HSP90 complexes to act on p53, but don't recall the details.

EDIT, just looked at the 2013 ASCO poster:

www.cellceutix.com/s/ASCO-poster-Kevetrin-2013-JUN-03-FINAL.pdf

and it appears that kevetrin as an HDAC inhibitor leads to acetylation of HSP90, blocking the stabilization of mutant p53, leading to its ubiquitination and eventual destruction.

I hope the current K-OC Phase II trial gets at some of these complex MOAs of kevetrin.

Perhaps an HSP90 inhibitor or some anti-metastatic agents will be synergistic with kevetrin wtp53 activator, similar to this study of an anti-HSP90 with Nutlin-3a:

https://www.ncbi.nlm.nih.gov/pubmed/26743233

Molecular biology especially related to cancer is so complicated and interesting. Here's hoping we can find some good drugs to kill cancer and stop it from spreading.