In This Issue pubs.acs.org/acsmedchemlett
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ANTIBODY−DRUG CONJUGATE AGAINST MULTIDRUG-RESISTANT TUMORS Potent chemotherapeutic anticancer agents conjugated with antibodies for specificity and selectivity are emerging as a novel class of targeted treatments. Antibody−drug conjugates (ADCs) previously failed due to low drug potency, unstable linkers, and low antigen selectivity. Further, the diversity of drugs available for ADCs is limited. The tubulysins have emerged as excellent payloads for ADCs due to high potency. The tubulysins are microtubule inhibiting small molecules with potent activity against multidrug-resistant carcinoma cell lines. In this issue, Staben et al. (DOI: 10.1021/acsmedchemlett.7b00243) report a strategy to prepare stable, effective and bioreversible ADCs using modified tubulysins as payload against multidrug-resistant lymphoma cell line and tumors. The authors successfully designed ADCs with a peptide trigger and a quaternary ammonium salt linker linked to the tertiary amine of tubulysin. The resulting ADC showed dose-dependent multidrug-resistant tumor growth inhibition in a mouse model with improved tolerability. These results pave the way for further investigation of this antitumor ADC.
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DISCOVERY OF MGLU7/8 RECEPTOR POSITIVE ALLOSTERIC MODULATOR The metabotropic glutamate receptors (mGlu) play an important role in physiology and pathophysiology of the central nervous system. Recently, mGlu7 has arisen as a target for the treatment of anxiety, depression, epilepsy, schizophrenia, and drug dependence; however, selective mGlu7 small molecule tools to study the receptor are lacking. In the present issue, Abe et al. (DOI: 10.1021/ acsmedchemlett.7b00317) report the structure−activity relationship studies of a series of pyrazolo[1,5-a]pyrimidine-based mGlu7 positive allosteric modulators (PAMs). Starting from a HTS campaign, the authors identified selective mGlu7 modulator with CNS penetration and potential for optimization. SAR studies were performed and DMPK profiles analyzed for the analogue series, leading to the identification of a dual mGlu7/8 PAM and the first mGlu7 preferring PAM. This study provides important tool compounds for exploration of Group III mGlu receptors, and further development is currently ongoing.
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SELECTIVE GRP94 INHIBITOR TARGETING S2 SUBPOCKET The Hsp90 isoform glucose regulated protein 94 (Grp94) is expressed in the endoplasmic reticulum and is implicated in various diseases, including hepatocellular carcinoma, multiple myeloma, rheumatoid arthritis, and glaucoma. Current investigational Hsp90 inhibitors lack selectivity and the design of selective inhibitors of Grp94 is challenging as the Hsp90 isoforms share more than 85% identity within their N-terminal ATP-binding site. Interestingly, Grp94 contains two unique subpockets that make it distinct from the other Hsp90 isoforms and provides a potential avenue for selective inhibitor design. Herein, Khandelwal et al. (DOI: 10.1021/acsmedchemlett.7b00193) disclose the first resorcinol-based selective Grp94 inhibitors, which target the S2 subpocket within the ATPbinding pocket. Starting with a resorcinol-containing lead compound, SAR studies yielded two inhibitors with more than 10-fold selectivity for Grp94 and nanomolar affinity. Furthermore, the lead compounds inhibited proliferation of multiple myloma cells. The study demonstrates the amenability of the Grp94 S2 subpocket for design of potent and selective inhibitors and shows potential for further development of resorcinol-based small molecules against this emerging target. © 2017 American Chemical Society
Published: October 12, 2017 988
DOI: 10.1021/acsmedchemlett.7b00388 ACS Med. Chem. Lett. 2017, 8, 988−988
