7 research outputs found
Characterization of the Menin-MLL Interaction as Therapeutic Cancer Target
Inhibiting the interaction of menin with the histone methyltransferase MLL1 (KMT2A) has recently emerged as a novel therapeutic strategy. Beneficial therapeutic effects have been postulated in leukemia, prostate, breast, liver and in synovial sarcoma models. In those indications, MLL1 recruitment by menin was described to critically regulate the expression of disease associated genes. However, most findings so far rely on single study reports. Here we independently evaluated the pathogenic functions of the menin-MLL interaction in a large set of different cancer models with a potent and selective probe inhibitor BAY-155. We characterized the inhibition of the menin-MLL interaction for anti-proliferation, gene transcription effects, and for efficacy in several in vivo xenografted tumor models. We found a specific therapeutic activity of BAY-155 primarily in AML/ALL models. In solid tumors, we observed anti-proliferative effects of BAY-155 in a surprisingly limited fraction of cell line models. These findings were further validated in vivo. Overall, our study using a novel, highly selective and potent inhibitor, shows that the menin-MLL interaction is not essential for the survival of most solid cancer models. We can confirm that disrupting the menin-MLL complex has a selective therapeutic benefit in MLL-fused leukemia. In solid cancers, effects are restricted to single models and more limited than previously claimed
Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target
MTH1
is a hydrolase responsible for sanitization of oxidized purine
nucleoside triphosphates to prevent their incorporation into replicating
DNA. Early tool compounds published in the literature inhibited the
enzymatic activity of MTH1 and subsequently induced cancer cell death;
however recent studies have questioned the reported link between these
two events. Therefore, it is important to validate MTH1 as a cancer
dependency with high quality chemical probes. Here, we present BAY-707,
a substrate-competitive, highly potent and selective inhibitor of
MTH1, chemically distinct compared to those previously published.
Despite superior cellular target engagement and pharmacokinetic properties,
inhibition of MTH1 with BAY-707 resulted in a clear lack of <i>in vitro</i> or <i>in vivo</i> anticancer efficacy
either in mono- or in combination therapies. Therefore, we conclude
that MTH1 is dispensable for cancer cell survival
Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target
MTH1
is a hydrolase responsible for sanitization of oxidized purine
nucleoside triphosphates to prevent their incorporation into replicating
DNA. Early tool compounds published in the literature inhibited the
enzymatic activity of MTH1 and subsequently induced cancer cell death;
however recent studies have questioned the reported link between these
two events. Therefore, it is important to validate MTH1 as a cancer
dependency with high quality chemical probes. Here, we present BAY-707,
a substrate-competitive, highly potent and selective inhibitor of
MTH1, chemically distinct compared to those previously published.
Despite superior cellular target engagement and pharmacokinetic properties,
inhibition of MTH1 with BAY-707 resulted in a clear lack of <i>in vitro</i> or <i>in vivo</i> anticancer efficacy
either in mono- or in combination therapies. Therefore, we conclude
that MTH1 is dispensable for cancer cell survival