Editors' ChoiceCancer

Targeting the cancer cells that just won’t go away

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Science Translational Medicine  22 Jun 2016:
Vol. 8, Issue 344, pp. 344ec101
DOI: 10.1126/scitranslmed.aag2112

Chromatin structure and gene expression are regulated in part through histone lysine methylation, the deregulation of which can contribute to cancer development and progression. In particular, the lysine demethylase 5 (KDM5) enzymes, KDM5A-D, have been implicated in the survival of drug-tolerant persister cells that resist treatment with targeted and cytotoxic therapies, making KDM5 enzymes high priority targets for drug discovery. However, these efforts have been hampered by the fact that KDM5 demethylases contain a funnel-shaped active site in which binding of the charged substrate 2-oxoglutarate (2-OG) is coordinated by a catalytic iron ion and polar amino acids, structural features that have impeded the design of selective and potent inhibitors. As a result, only nonselective metal-chelating or 2-OG competitive inhibitors have been described to date.

A team of scientists at Genentech and Constellation Pharmaceuticals took on this problem by using a high-throughput mass spectrometry-powered approach to identify compounds with activity against the enzymatic domain of a related enzyme, KDM4C. Chemically tractable compounds emerging from this screen were then optimized for potency and selectivity against KDM5 family members. The resulting lead compound, CPI-455, exhibited potent inhibition of KDM5 family members in enzymatic and cellular assays and over 200-fold selectivity for KDM5 enzymes relative to KDM2, 3, 4, 6, and 7 enzymes. Crystallographic studies revealed the structure of KDM5A both alone and in the presence of CPI-455, confirming that this drug directly competes with 2-OG binding and yielding insights into the mechanism of selectivity of the drug. Last, studies in multiple oncogene-driven cancer models suggested that CPI-455 caused global and reversible increases in histone H3 lysine 4 trimethylation and selectively targeted drug-tolerant persister cells, which have increased KDM5A expression and depend on KDM5A demethylase activity for their survival.

Through both structural insights and the development of CPI-455, this work paves the way for fundamental mechanistic studies to dissect the role of KDM5 family enzymes in diverse biological processes. These studies also add to the growing armamentarium of selective inhibitors of epigenetic processes important for cancer progression and lay essential groundwork for future studies to evaluate whether KDM5 family inhibition can improve therapeutic responses in animal models and, ultimately, human patients.

M. Vinogradova et al., An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat. Chem. Biol. 10.1038/nchembio.2085 (2016). [Abstract]

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