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Pim kinases are promising targets in the treatment of hematopoietic and solid cancers. Meridianin C was chosen as a starting point to discover novel pim kinase inhibitors. Using known pim kinase's structural information, aminopyrimidine was introduced to provide the hydrogen-bonding interactions with the conserved lysine residue in the ATP binding pocket of all three Pim kinases. Synthesized 3,5-bis(aminopyrimidinyl)indole derivatives showed pan-pim inhibitory activity. Aminoalkyl substituent was attached on the aminopyrimidine to further enhance the potency and physicochemical properties of compound. The research reveals a significative way of designing compounds with high potency and kinase selectivity for pan-pim kinases. [ABSTRACT FROM AUTHOR]

Xanthene fluorophores, including fluorescein, rhodol, and rhodamines, are representative classes of fluorescent probes that have been applied in the detection and visualization of biomolecules. "Turn on" activatable fluorescent probes, that can be turned on in response to enzymatic reactions, have been developed and prepared to reduce the high background signal of "always-on" fluorescent probes. However, the development of activity-based fluorescent probes for biological applications, using simple xanthene dyes, is hampered by their inefficient synthetic methods and the difficulty of chemical modifications. We have, thus, developed a highly efficient, versatile synthetic route to developing chemically more stable reduced xanthene fluorophores, based on fluorescein, rhodol, and rhodamine via continuous Pd-catalyzed cross-coupling. Their fluorescent nature was evaluated by monitoring fluorescence with variation in the concentration, pH, and solvent. As an application to activatable fluorescent probe, nitroreductase (NTR)-responsive fluorescent probes were also developed using the reduced xanthene fluorophores, and their fluorogenic properties were evaluated. [ABSTRACT FROM AUTHOR]

Heat-shock protein 90 (HSP90) is a molecular chaperone that activates oncogenic transformation in several solid tumors, including lung and breast cancers. Ganetespib, a most promising candidate among several HSP90 inhibitors under clinical trials, has entered Phase III clinical trials for cancer therapy. Despite numerous evidences validating HSP90 as a target of anticancer, there are few studies on PET agents targeting oncogenic HSP90. In this study, we synthesized and biologically evaluated a novel 18 F-labeled 5-resorcinolic triazolone derivative (1, [ 18 F]PTP-Ganetespib) based on ganetespib. [ 18 F]PTP-Ganetespib was labeled by click chemistry of Ganetespib-PEG-Alkyne (10) and [ 18 F]PEG-N 3 (11) with 37.3 ± 5.11% of radiochemical yield and 99.7 ± 0.09% of radiochemical purity. [ 18 F]PTP-Ganetespib showed proper LogP (0.96 ± 0.06) and good stability in human serum over 97% for 2 h. [ 18 F]PTP-Ganetespib showed high uptakes in breast cancer cells containing triple negative breast cancer (TNBC) MDA-MB-231 and Her2-negative MCF-7 cells, which are target breast cancer cell lines of HSP90 inhibitor, ganetespib, as an anticancer. Blocking of HSP90 by the pretreatment of ganetespib exhibited significantly decreased accumulation of [ 18 F]PTP-Ganetespib in MDA-MB-231 and MCF-7 cells, indicating the specific binding of [ 18 F]PTP-Ganetespib to MDA-MB-231 and MCF-7 cells with high HSP90 expression. In the biodistribution and microPET imaging studies, the initial uptake into tumor was weaker than in other thoracic and abdominal organs, but [ 18 F]PTP-Ganetespib was retained relatively longer in the tumor than other organs. The uptake of [ 18 F]PTP-Ganetespib in tumors was not sufficient for further development as a tumor-specific PET imaging agent by itself, but this preliminary PET imaging study of [ 18 F]PTP-Ganetespib can be basis for developing new PET imaging agents based on HSP90 inhibitor, ganetespib., (Copyright © 2018 Elsevier Ltd. All rights reserved.)