Supplementary Materials and Methods, Supplementary Table 1, and Supplementary Figure Legends from Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines <i>In Vitro</i> and <i>In Vivo</i>

PDF - 126K, Includes the methods for preparation of TAI-95, drug-drug synergy experiments, and preliminary subacute toxicology, Table S1: Combination index of TAI-95 with anticancer agents, and supplementary figure legends.</p

Supplementary Figures 1 through 6 from Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines <i>In Vitro</i> and <i>In Vivo</i>

PDF - 1333K, Figure S1. Summary of structural modifications. Figure S2. Hec1 localization. Figure S3. Activation of apoptosis. Figure S4. Subacute toxicity study: histological sections. Figure S5. Subacute toxicity study: organ weight and blood indices. Figure S6. Additional breast cancer xenograft mouse models.</p

Discovery of 4‑Aryl‑<i>N</i>‑arylcarbonyl-2-aminothiazoles as Hec1/Nek2 Inhibitors. Part I: Optimization of in Vitro Potencies and Pharmacokinetic Properties

A series of 4-aryl-<i>N</i>-arylcarbonyl-2-aminothiazoles of scaffold <b>4</b> was designed and synthesized as Hec1/Nek2 inhibitors. Structural optimization of <b>4</b> led to compound <b>32</b> bearing C-4′ 4-methoxyphenoxy and 4-(<i>o</i>-fluoropyridyl)­carbonyl groups that showed low nanomolar in vitro antiproliferative activity (IC₅₀: 16.3–42.7 nM), high intravenous AUC (64.9 μM·h, 2.0 mg/kg) in SD rats, and significant in vivo antitumor activity (T/C = 32%, 20 mg/kg, IV) in mice bearing human MDA-MB-231 xenografts. Cell responses resulting from Hec1/Nek2 inhibition were observed in cells treated with <b>32</b>, including a reduced level of Hec1 coimmunoprecipitated with Nek2, degradation of Nek2, mitotic abnormalities, and apoptosis. Compound <b>32</b> showed selectivity toward cancer cells over normal phenotype cells and was inactive in a [³H]­astemizole competitive binding assay for hERG liability screening. Therefore, <b>32</b> is as a good lead toward the discovery of a preclinical candidate targeting Hec1/Nek2 interaction

Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile

A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots