Why care about p97?
In my postdoc work, I participated in a large team effort at designing a small molecule inhibitor of the p97 AAA-ATPase.
The funding for this project came from the National Cancer Institute (NCI) and was premised on the idea that inhibiting p97 in certain types of cancer cells that depend heavily on the endoplasmic-reticulum associated degradation pathway (ERAD) would have the effect of triggering the unfolded-protein response and apoptosis pathways within the rapidly growing tumor cell populations. This is because p97 is a critical regulator and component of ERAD, and when it is inhibited, the cell experiences unbalanced protein homeostasis and unfolded protein stress.
Drug design is an extremely challenging problem, and even with a large group of researchers it took us several years to find a compound that showed promising inhibition against p97. Our results were published in ACS Med Chem Letters in 2016. The compound we discovered, indole amide 3, has high solubility, permeability, and stability. It binds an allosteric site on the D2 domain with sub-micromolar affinity. Unfortunately, it just didn’t have enough binding affinity to be active in vivo.
A different approach yields new promise
At around the same time we were developing our allosteric inhibitor series, another group was developing an ATP competitive D2 domain inhibitor of p97, called CB-5083. In contrast to our compound, this one binds directly to the D2 ATP enzyme site with nanomolar affinity.
The compound also demonstrated potent and specific p97 inhibition activity in mouse xenograft models of tumors.
An advance in myeloma cancer therapy
A more recent paper (Nov 2017) shows activity for CB-5083 against multiple myeloma (MM) cell lines and in vivo MM models. From the abstract:
CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents.
Standard of care agents, like bortezomib, are proteasome inhibitors (PI). Using a PI results in broad inhibition of the proteasome system across many cell types, not just tumor cells, and thus a high likelihood of side effects. p97 is upstream of the proteasome and targeting it is more narrow in scope, because MM cells rely so heavily on the protein homeostasis activities of the ERAD pathway.
Hope for Phase 1 success
CB-5083 was also found to enhance the activity of bortezomib both in vitro and in vivo and also was active in bortezomib-resistance models of MM. This paves the way for a potential combination therapy or another line of therapy if resistance develops as a result of earlier treatment with PIs. Clinical trials are now ongoing in Phase 1 for patients who have exhausted other medications. Hopefully CB-5083 makes it to the market soon, if trials prove it to be safe and efficacious, so that oncologists and patients have another weapon in the fight against MM.