title: Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy.
abstract: 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.
authors.affiliation: Cell Biology Department, BU Oncology, Nerviano Medical Sciences, v.le Pasteur 10, Nerviano, Milan 20014, Italy. Clara.Albanese@nervianoms.com
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.forename: Rachele
authors.initials: R
authors.lastname: Alzani
authors.forename: Nadia
authors.initials: N
authors.lastname: Amboldi
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Locatelli
authors.forename: Wilma
authors.initials: W
authors.lastname: Pastori
authors.forename: Veronica
authors.initials: V
authors.lastname: Patton
authors.forename: Fulvia
authors.initials: F
authors.lastname: Roletto
authors.forename: Francesco
authors.initials: F
authors.lastname: Colotta
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Jurgen
authors.initials: J
authors.lastname: Moll
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
mesh_terms: 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
chemical_list: 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