| Reference | 1. Br J Pharmacol. 2013 May;169(1):156-66. doi: 10.1111/bph.12112.
<br>
Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor
able to cross the blood-brain barrier.
<br>
Albanese C(1), Alzani R, Amboldi N, Degrassi A, Festuccia C, Fiorentini F,
Gravina G, Mercurio C, Pastori W, Brasca M, Pesenti E, Galvani A, Ciomei M.
<br>
Author information: <br>
(1)BU Oncology, Nerviano Medical Sciences, Nerviano, Milan, Italy.
[email protected]
<br>
BACKGROUND AND PURPOSE: Malignant gliomas, the most common primary brain tumours,
are highly invasive and neurologically destructive neoplasms with a very bad
prognosis due to the difficulty in removing the mass completely by surgery and
the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase
inhibitor with broad anti-tumour activity in pre-clinical studies and good
tolerability in phase 1 studies, which could affect two main pathways involved in
glioma pathogenesis, the G1-S phase progression control pathway through the
inhibition of cyclin-dependent kinases and the signalling pathways mediated by
tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this
reason, we tested PHA-848125 in glioma models.<br>
EXPERIMENTAL APPROACH: PHA-848125 was tested on a panel of glioma cell lines in
vitro to evaluate inhibition of proliferation and mechanism of action. In vivo
efficacy was evaluated on two glioma models both as single agent and in
combination with standard therapy.<br>
KEY RESULTS: When tested on a subset of representative glioma cell lines,
PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell
cycle and signal transduction markers. Relevantly, PHA-848125 was also able to
induce cell death through autophagy in all cell lines. Good anti-tumour efficacy
was observed by oral route in different glioma models both with s.c. and
intracranial implantation. Indeed, we demonstrate that the drug is able to cross
the blood-brain barrier. Moreover, the combination of PHA-848125 with
temozolomide resulted in a synergistic effect, and a clear therapeutic gain was
also observed with a triple treatment adding PHA-848125 to radiotherapy and
temozolomide.<br>
CONCLUSIONS AND IMPLICATIONS: All the pre-clinical data obtained so far suggest
that PHA-848125 may become a useful agent in chemotherapy regimens for glioma
patients and support its evaluation in phase 2 trials for this indication.
<br>
2. Pharmacol Res. 2010 May;61(5):437-48. doi: 10.1016/j.phrs.2009.12.009. Epub 2009
Dec 21.
<br>
The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth
of human melanomas sensitive or resistant to temozolomide, and shows synergistic
effects in combination with this triazene compound.
<br>
Caporali S(1), Alvino E, Starace G, Ciomei M, Brasca MG, Levati L, Garbin A,
Castiglia D, Covaciu C, Bonmassar E, D/’Atri S.
<br>
Author information: <br>
(1)Laboratory of Molecular Oncology, Istituto Dermopatico dell/’Immacolata-IRCCS,
Via dei Monti di Creta 104, 00167 Rome, Italy.
<br>
PHA-848125 is a novel cyclin-dependent kinase inhibitor under Phase I/II clinical
investigation. In this study, we describe, for the first time, the effect of
PHA-848125 on human melanoma cells in vitro. Seven melanoma cell lines with
different sensitivity to temozolomide (TMZ) were exposed to PHA-848125 for 5 days
and then assayed for cell growth. In all cases, including TMZ-resistant cells,
PHA-848125 IC(50) values were significantly below the maximum plasma
concentrations achievable in the clinic. In the most PHA-848125-sensitive cell
line, the drug caused a concentration-dependent G(1) arrest. PHA-848125 also
impaired phosphorylation of the retinoblastoma protein at CDK2 and CDK4 specific
sites, decreased retinoblastoma protein and cyclin A levels, and increased
p21(Cip1), p27(Kip1) and p53 expression. Combined treatment with fixed ratios of
TMZ plus PHA-848125 was studied in three melanoma cell lines. PHA-848125 was
added to the cells 48 h after TMZ and cell growth was evaluated after 3
additional days of culture. Parallel experiments were performed in the presence
of O(6)-benzylguanine (BG), to prevent repair of methyl adducts at O(6)-guanine
induced by TMZ. Drug combination of TMZ plus BG and PHA-848125 produced additive
or synergistic effects on cell growth, depending on the cell line. In the absence
of BG, the combination was still more active than the single agents in the cell
line moderately sensitive to TMZ, but comparable to PHA-848125 alone in the two
TMZ-resistant cell lines. When TMZ plus BG were used in combination with
PHA-848125 against cultured normal melanocytes, neither synergistic nor additive
antiproliferative effects were observed. Our results indicate that PHA-848125 can
have a therapeutic potential in melanoma patients, alone or combined with TMZ.
Moreover this agent appears to be particularly attractive on the bases of its
effectiveness against TMZ-resistant melanoma cells.
<br>
3. J Med Chem. 2009 Aug 27;52(16):5152-63. doi: 10.1021/jm9006559.
<br>
Identification of
N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-py
razolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available
cyclin dependent kinase inhibitor.
<br>
Brasca MG(1), Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M,
Colotta F, Croci V, D/’Alessio R, Fiorentini F, Isacchi A, Mercurio C, Moretti W,
Panzeri A, Pastori W, Pevarello P, Quartieri F, Roletto F, Traquandi G, Vianello
P, Vulpetti A, Ciomei M.
<br>
Author information: <br>
(1)Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014
Nerviano (MI), Italy. [email protected]
<br>
The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs)
is described. Starting from compound 1, showing good potency as inhibitor of CDKs
but being poorly selective against a panel of serine-threonine and tyrosine
kinases, new analogues were synthesized. Enhancement in selectivity,
antiproliferative activity against A2780 human ovarian carcinoma cells, and
optimization of the physical properties and pharmacokinetic profile led to the
identification of highly potent and orally available compounds. Compound 28
(PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma
model showed good efficacy and was well tolerated upon repeated daily treatments,
was identified as a drug candidate for further development. Compound 28 is
currently undergoing phase I and phase II clinical trials.
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