MTH1: From Hot Topic To Devalidation?

Includes: AZN, BAYRY
by: Derek Lowe

Here's an argument that's been going on inside the oncology drug development world over the last few years: is the enzyme MTH1 a great cancer target or a complete waste of time? MTH1, also known as NUDT1, degrades phosphates of 8-oxoguanine, an oxidized form of the regular guanine that cells know and love. That enzymatic activity keeps the oxoguanine from being incorporated into DNA, where it is definitely not a completely functional replacement for regular G. Such incorporation has been noted as a side effect of aging in animal models, and the theory has been that some cancer lines also depend on MTH1 to keep the nucleotide supply cleaned up while their do their rapid-division phenotype. Given the importance of DNA repair enzymes and related systems in tumor biology, this sort of prep work seems to be a reasonable idea.

In 2014, papers came out from researchers in Sweden and a Sweden/Austria/UK collaboration with strong evidence for that hypothesis. Both of them showed small molecule inhibitors of MTH1 (with crystal structures) and demonstrated that they had strong effects on various cancer cell types. These reports were followed, though, by others saying that MTH1 inhibitors didn't seem to show such activity at all. Some of the original researchers responded in this 2016 paper, saying that the problem was that the cellularly-inactive compounds turned out not to actually lead to oxidized nucleotides being incorporated into DNA, but why that should be the case was still a mystery:

Here, we cannot give an explicit biochemical explanation to why the potent MTH1 inhibitors previously described by Kettle and Petrocchi do not result in incorporation of 8-oxodG into DNA nor why they do not kill cancer cells. There are four different isoforms of MTH1, which can be differentially inhibited by various MTH1 inhibitors (data not shown) and there are further emerging post-translational modifications on MTH1 that may affect the efficiency of MTH1 inhibition. Clearly, more in depth understanding of the complex MTH1 biology is required to answer these questions. Another possibility is that the TH588 and TH1579 compounds have relevant off-target effects, which work together with MTH1 inhibition to provide the cell killing effects.

The AstraZeneca (NYSE:AZN) paper that failed to validate MTH1 had suggested just that latter possibility: that the activity of such compounds as TH588, from the Swedish group, might well just be due to off-target cytotoxic effects. Now a group from Bayer (OTCPK:BAYRY) has jumped into the controversy with a new paper that also fails to validate the whole concept:

Attractive target rationale combined with previous success in identifying potent and cellularly active inhibitors prompted us to develop novel MTH1 matter. We developed structurally distinct, potent and selective MTH1 inhibitors with high solubility, metabolic stability, cell permeability and cellular target engagement. However, these properties did not translate into in vitro or in vivo anti-cancer efficacy either in mono- or in combination-therapies. Based on these observations we concluded MTH1 is not essential for cancer cell survival or for intracellular sanitization of damaged nucleotides and thus not a viable target to be exploited for drug development.

What's more, when they compared their own compound (BAY-707) to the previously reported TH588, they could not reproduce the blood levels reported for the latter compound, found it to be quite insoluble, and could not demonstrate any activity in three different animal models with it. BAY-707 itself had far better pharmacokinetics, but treatment in two different xenograft models, alone or in combination with radiation or three other standard chemotherapies, showed no effect at all for MTH1 inhibition. The Bayer group also notes that MTH1 knockout mice seem to display no phenotypic differences to wild-type. That's not always a solid indicator, due to developmental compensation, but taken together with the pharmacologic results it has be considered another mark against the target. They're ready to throw dirt on the grave of the whole idea:

Identifying the right targets is of utmost importance for drug discovery in the era of targeted therapies. It relies on the quality of chemical probes, knockdown and knockout reagents with minimized off-target activities. In this study we describe a novel class of highly potent MTH1 inhibitors, which despite superior biochemical potency, cellular target engagement and pharmacokinetic profile to other MTH1 tool compounds, exert no in vitro or in vivo anti-cancer efficacy either in mono- or in combination-therapies. With BAY-707, a representative member of this compound class, we de-validate MTH1 as a broad-spectrum non- oncogenic cancer dependency and provide the scientific community with a chemical probe having no off-target-related cytotoxicity, to elucidate the biology of MTH1 in cell cultures and living organisms.

As for the idea that some MTH1 inhibitors somehow don't allow oxo-guanine incorporation into DNA, the Bayer group found that BAY-707 did indeed demonstrate this effect, while TH588 did show the production of the altered DNA. But they went on to show that this doesn't seem to have anything to do with the MTH1 pathway - you can get the same effect by treatment of cells with several other distinct cytotoxic drugs, or even with siRNAs directed toward other targets than MTH1. So rather than this being a complication of MTH1 biology, as the earlier response suggested, it seems to be just an artifact that has nothing to do with the target at all.

After all this, I have to agree with the conclusion that MTH1 is not a valid cancer target. The whole story is a good illustration of how what looks like a perfectly reasonable idea, backed up with what seems to be higher-than-usual amount of solid data, can still turn out to be completely mistaken. It also show just how complicated it can be to unravel what's really happening inside cells, and the critical importance of good small-molecule probes, thoroughly characterized, in answering those questions. There are pitfalls and complications waiting everywhere, and new ideas like this one have to be checked from every angle you can think of. Kick the tires, slam the doors - it's the only way.

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