In This Issue pubs.acs.org/acsmedchemlett
■
■
USING FISH TO EVALUATE PROTECTION FROM NEUROTOXINS Parkinson’s disease is a progressive neurodegenerative disorder that affects movement. Symptoms of the disease include tremors, loss of automatic movements, impaired balance, and slowed movement. Although Parkinson’s disease is among the most common neurodegenerative disorders affecting the elderly, the causes of Parkinson’s disease are largely unknown. Evidence suggests that exposure to neurotoxins can be a contributing factor causing disease. In this month’s Featured Letter (DOI: 10.1021/acsmedchemlett.5b00372), Li et al. examine the chemistry and biological consequences of complex formation of a synthetic receptor cucurbit[7]uril (CB[7]) and neurotoxins. Using a zebrafish model of neurotoxin-induced neurodegeneration that monitors swimming behavior in the presence and absence of neurotoxin, the authors demonstrate that CB(7) is able to protect neurons from degeneration and effectively attenuates the effects of neurotoxins on swimming behavior. The findings presented here represent a novel approach for reducing the neurodegenerative effects of neurotoxins that may lead to disorders such as Parkinson’s disease.
TOWARD VALIDATING P97 AS A CLINICAL CANCER TARGET The AAA ATPase p97 is known to play a role in a variety of cellular processes. Notably, p97 is upregulated in a number of cancers including breast, lung, pancreatic, and colorectal cancer, thus suggesting that p97 may serve as a potential therapeutic target for cancer. Unfortunately, no suitable p97 antagonists have been identified that would allow for validation of p97 as a cancer target in a clinical setting. In this issue, Alverez et al. (DOI: 10.1021/acsmedchemlett.5b00364) prepared a C-5 trifluoromethylated indole and five isosteres of the trifluoromethyl group as part of a medicinal chemistry effort to identify suitable p97 inhibitors and develop them as potential anticancer therapeutics. The authors describe the synthesis of these six indole derivatives and report on detailed structure−activity relationships for these compounds. Moreover, the work discloses a new chemotype for the inhibition of the cancer-relevant AAA ATPase p97.
■
MAKING A BETTER PAK1 INHIBITOR Overexpression of the p21-activated kinase PAK1 has been observed in several types of cancer and, in particular, is associated with poor prognosis in patients with luminal breast cancer. Inhibitors of PAK1 have been identified as potential anticancer agents and have even entered to clinical trials; however, progression through clinical trials has not been successful to date. The letter by Ndubaku et al. (DOI: 10.1021/acsmedchemlett.5b00398) describes efforts to improve the properties of a known PAK1 inhibitor, FRAX1036, to generate compounds more suited for clinical utility. The advanced compound developed here demonstrated increased PAK1 potency in enzymatic and cellular assays and improved pharmacokinetics compared to the parent compound and selectivity toward a range of kinases and off-targets. The authors use tumor xenograft mice to evaluate pharmacokinetic and pharmacodynamic properties of the compound demonstrating dose-dependent inhibition of the PAK1 pathway.
Published: December 10, 2015 © 2015 American Chemical Society
1167
DOI: 10.1021/acsmedchemlett.5b00446 ACS Med. Chem. Lett. 2015, 6, 1167−1167
