NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies.
Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings.
Nerviano Medical Sciences Srl, Nerviano, Milan, Italy. barbara.valsasina@nervianoms.com
Barbara
B
Valsasina
Italo
I
Beria
Cristina
C
Alli
Rachele
R
Alzani
Nilla
N
Avanzi
Dario
D
Ballinari
Paolo
P
Cappella
Michele
M
Caruso
Alessia
A
Casolaro
Antonella
A
Ciavolella
Ulisse
U
Cucchi
Anna
A
De Ponti
Eduard
E
Felder
Francesco
F
Fiorentini
Arturo
A
Galvani
Laura M
LM
Gianellini
Maria L
ML
Giorgini
Antonella
A
Isacchi
Jaqueline
J
Lansen
Enrico
E
Pesenti
Simona
S
Rizzi
Maurizio
M
Rocchetti
Francesco
F
Sola
Jürgen
J
Moll
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D005260:Female; D018922:HL-60 Cells; D000882:Haplorhini; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011799:Quinazolines; D000097869:Polo-Like Kinase 1; C560415:NMS P937