ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models.
OBJECTIVE
Profiling the efficacy and pharmacodynamic activity of the kinesin spindle protein (KSP) inhibitor ARRY-520 will aid the identification of responsive tumor types and pharmacodynamic profiles that correlate with activity.


METHODS
In vivo activity was evaluated in a diverse panel of 16 different tumor xenograft models. Pharmacodynamic activity was evaluated in selected models.


RESULTS
ARRY-520 had low nanomolar antiproliferative activity in tumor cell lines. Monopolar spindles were formed at active potencies. Partial or complete responses were observed in 13/16 xenograft models. Hematological tumors were particularly sensitive, with a 100% complete response rate in some models. Maintenance of mitotic block for a sufficient length of time for cells to lose survival signals and progress to apoptosis was a key component of the mechanism of activity. ARRY-520 was also active in several taxane resistant models.


CONCLUSIONS
The data provide a rationale for clinical evaluation of the activity of ARRY-520 in hematological carcinomas and taxane-resistant tumors.
Woessner
Richard
R
Department of Pharmacology, Array BioPharma Inc., Boulder, CO 80301, USA. richard.woessner@arraybiopharma.com
Tunquist
Brian
B
Lemieux
Christine
C
Chlipala
Elizabeth
E
Jackinsky
Steve
S
Dewolf
Walter
W
Voegtli
Walter
W
Cox
April
A
Rana
Sumeet
S
Lee
Patrice
P
Walker
Duncan
D
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D019070:Cell Lineage; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D045325:HCT116 Cells; D018922:HL-60 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D020014:K562 Cells; D016547:Kinesins / Q000037:antagonists & inhibitors*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D043823:Taxoids / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C470243:KIF11 protein, human; D043823:Taxoids; D013830:Thiadiazoles; C544550:filanesib; D016547:Kinesins