In This Issue pubs.acs.org/acsmedchemlett
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AN UNUSUAL APPROACH REVEALS A NOVEL DOT1L INHIBITOR
Recently, the histone methyltransferase Dot1L has emerged as an attractive target for the treatment of certain leukemias. The quest for Dot1L inhibitors culminated in the identification of a compound that is structurally related to the cofactor S-adenosylmethionine (SAM). In clinical trials, this compound is being administered by uninterrupted, continuous intravenous infusion, and compounds with physicochemical properties that allow for improved delivery mechanisms are being sought. In the article featured on the cover of this month’s issue, Chen et al. (DOI: 10.1021/acsmedchemlett.6b00167) describe the discovery of the first potent and orally available Dot1L inhibitor. From a high-throughput screen, the authors identified a hit found to bind a novel induced pocket adjacent to the SAM binding site. The chemical starting point was evolved by an unusual growing−fragmentation−growing approach, strongly supported by protein structural information. In addition to presenting the discovery of structurally novel, potent, and selective Dot1L inhibitors, this work provides new insight into the conformational flexibility of Dot1L, revealing novel binding pockets that are utilized for the identification of Dot1L inhibitors structurally unrelated to SAM.
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A NEW PROBE FOR IN VIVO INVESTIGATIONS OF MTOR ACTIVITY Mammalian target of rapamycin (mTOR) is a central regulator involved in a number of processes including metabolism, and dysregulation of mTOR signaling may result in inflammatory diseases, metabolic diseases, and cancer. Although several ATPcompetitive mTOR inhibitors have previously been described, many of these inhibitors either display limited selectivity or are only partially characterized and are not suitable as in vivo probes. In order to generate meaningful biological data, multiple selective probes with well-defined modes of action should be used. In this issue, Bergamini et al. (DOI: 10.1021/acsmedchemlett.6b00149) identify a selective mTOR inhibitor with efficacy in a collagen induced arthritis model. The authors describe a comprehensive biological and pharmacological characterization validating the compound as a potential tool for the pharmacological investigation of mTOR in vivo.
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OVERCOMING TKI RESISTANCE Research in the field of cancer therapeutics is rapidly advancing; however, a large proportion of the gains made in this field are eroded by the emergence of drug resistance. For example, EGFR-tyrosine kinase inhibitors (TKI) are the drugs of choice for patients with nonsmall cell lung cancer; unfortunately, it is widely encountered that resistant cancer cells develop bypass pathways to evade the kinase target of these drugs. MET signaling is one such recurring pathway. MET kinase is able to localize to the mitochondria of cancer cells and evade inactivation by drugs used in resistant cases of lung cancer. Designing compounds that specifically target the total complement of MET in the cell, including MET in the mitochondria, thus eliminating resistant cells would present a mechanism to overcome resistance. In the proof of concept study presented here, Yang et al. (DOI: 10.1021/acsmedchemlett.6b00223) attach a mitochondria targeting motif to a known MET kinase inhibitor in an effort to overcome resistance. The authors demonstrate that this approach can successfully deliver the conjugate to the mitochondria. Although the conjugate only partially suppressed the activation of MET in resistant cells, resistant cells were ultimately killed, thus suggesting this strategy to be a promising approach to overcome TKI resistance. © 2016 American Chemical Society
Published: August 11, 2016 724
DOI: 10.1021/acsmedchemlett.6b00295 ACS Med. Chem. Lett. 2016, 7, 724−724
