Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy.
Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC(50). PHA-848125-treated cells show cell cycle arrest in G(1) and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment.
Albanese
Clara
C
Cell Biology Department, BU Oncology, Nerviano Medical Sciences, v.le Pasteur 10, Nerviano, Milan 20014, Italy. Clara.Albanese@nervianoms.com
Alzani
Rachele
R
Amboldi
Nadia
N
Avanzi
Nilla
N
Ballinari
Dario
D
Brasca
Maria Gabriella
MG
Festuccia
Claudio
C
Fiorentini
Francesco
F
Locatelli
Giuseppe
G
Pastori
Wilma
W
Patton
Veronica
V
Roletto
Fulvia
F
Colotta
Francesco
F
Galvani
Arturo
A
Isacchi
Antonella
A
Moll
Jurgen
J
Pesenti
Enrico
E
Mercurio
Ciro
C
Ciomei
Marina
M
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D005810:Multigene Family; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C550092:N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide; D011720:Pyrazoles; D011799:Quinazolines; D011494:Protein Kinases; D018844:Cyclin-Dependent Kinases; C041311:tropomyosin kinase