1.Investigations on the antiproliferative effects of amino acid antagonists targeting for aminoacyl-tRNA synthetases. Part II--The antileukemic effect.
Laske R;Schönenberger H;Holler E Arch Pharm (Weinheim). 1989 Dec;322(12):857-62.
Amino acid antagonists with proven or potential inhibitory activities on aminoacyl-tRNA synthetases were tested for their antiproliferative effect against the murine leukemic cell line P388D1. Micromolar concentrations of the compounds S-tritylcysteine (18), fenitropan and beta-chloroalanine gave strong growth inhibition. In the mouse only 18 was effective against leukemia P388 (T/C = 211%). The inhibitory effect on aminoacyl-tRNA synthetases and the antiproliferative action on P388D1 or P388 could not be correlated.
2.Optimized S-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models.
Good JA;Wang F;Rath O;Kaan HY;Talapatra SK;Podgórski D;MacKay SP;Kozielski F J Med Chem. 2013 Mar 14;56(5):1878-93. doi: 10.1021/jm3014597. Epub 2013 Feb 27.
The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K(i)(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.
3.Integrity of the Pericentriolar Material Is Essential for Maintaining Centriole Association during M Phase.
Seo MY;Jang W;Rhee K PLoS One. 2015 Sep 25;10(9):e0138905. doi: 10.1371/journal.pone.0138905. eCollection 2015.
A procentriole is assembled next to the mother centriole during S phase and remains associated until M phase. After functioning as a spindle pole during mitosis, the mother centriole and procentriole are separated at the end of mitosis. A close association of the centriole pair is regarded as an intrinsic block to the centriole reduplication. Therefore, deregulation of this process may cause a problem in the centriole number control, resulting in increased genomic instability. Despite its importance for faithful centriole duplication, the mechanism of centriole separation is not fully understood yet. Here, we report that centriole pairs are prematurely separated in cells whose cell cycle is arrested at M phase by STLC. Dispersal of the pericentriolar material (PCM) was accompanied. This phenomenon was independent of the separase activity but needed the PLK1 activity. Nocodazole effectively inhibited centriole scattering in STLC-treated cells, possibly by reducing the microtubule pulling force around centrosomes. Inhibition of PLK1 also reduced the premature separation of centrioles and the PCM dispersal as well. These results revealed the importance of PCM integrity in centriole association.
