CW069

CW069 is a selective allosteric inhibitor of HSET with IC50 value of 75 μM [1].

HSET is a minus-end microtubule (MT) motor protein and is encoded by KIFC1 and Kifc5a in humans and mice, respectively. HSET plays an important role in the assembly of a functional mitotic spindle [1].

CW069 is a selective allosteric inhibitor of HSET. CW069 exhibited significant selectivity over KSP. In silico model for HSET binding, the highly favorable hydrogen bond formed between the carboxylate of CW069 and the guanidinium group of Arg521 in HSET. Also, a cation-πinteraction formed between the exposed phenyl group of CW069 and the Arg521 side chain. Arg521 was critical for CW069 selectivity. The enantiomer of CW069 bound more weakly to HSET due to a weak interaction between the carboxylate of the ligand and Arg521 in HSET. In N1E-115 cancer cells, CW069 significantly increased multipolar spindle formation due to a lack of centrosome clustering. In MDA-MB-231 and BT549 breast cancer cells, CW069 significantly increased multipolar spindles. In N1E-115 cells, CW069 (200 μM) induced multipolar anaphase formation and apoptosis [1].

Reference:
[1].  Watts CA, Richards FM, Bender A, et al. Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes. Chem Biol, 2013, 20(11): 1399-1410.