The
oral CHK1 inhibitors GDC-0425 and GDC-0575 have been reported in phase I
clinical trials. They have clear advantage on other CHK1 inhibitors in clinical
trials that are intravenous agents and have relatively low selectivity for CHK1.
Checkpoint Kinases (CHK) as Drug Targets
Individual
cells replicate by making an exact copy of their chromosomes, and then
segregating these into separate cells. This cycle of DNA replication,
chromosome separation and division is regulated by mechanisms within the cell
that maintain the order of the steps and ensure that each step is precisely
carried out. Involved in these processes are the cell cycle checkpoints where
cells may arrest to ensure DNA repair mechanisms have time to operate prior to
continuing through the cycle into mitosis. There are two such checkpoints in
the cell cycle-the G1/S checkpoint that is regulated by p53 and the G2/M
checkpoint that is monitored by the serine/threonine kinase Checkpoint kinase 1
(CHK1).
CHK1 and
CHK2 are structurally unrelated yet functionally overlapping serine/threonine
kinases activated in response to genotoxic stimuli. CHK1 and CHK2 relay the
checkpoint signals from the Ataxia telangiectasia mutated (ATM) and Ataxia
telangiectasia and RAD3-related (ATR), which phosphorylate and activate them.
CHK2 is
a stable protein expressed throughout the cell cycle, activated mainly by ATM
in response to double-strand DNA breaks (DSBs). In contrast, CHK1 protein
expression is largely restricted to S and G2 phases. In response to DNA damage,
CHK1 is phosphorylated and activated by ATM/ATR, resulting in cell cycle arrest
in the S and G2/M phases to allow for repair of DNA damage.
Inhibition
of CHK1 has been shown to abrogate cell cycle arrest leading to enhanced tumor
cell death following DNA damage by a range of chemotherapeutics. Cells lacking
intact G1 checkpoints are particularly dependent on S and G2/M checkpoints and
are therefore expected to be more sensitive to chemotherapeutic treatment in
the presence of a CHK1 inhibitor, whereas normal cells with functional G1
checkpoints would be predicted to undergo less cell death. Depending upon the
timing of DNA damage, CHK1 will arrest the cell in either the S or G2-phase.
These arrest points are called DNA damage checkpoints.
In the
presence of single-stranded DNA breaks or stalled replication forks, CHK1 is
activated resulting in cell cycle arrest, stabilization of replication origins
and suppression of apoptosis. This response acts rapidly to temporarily stall
the cell cycle to allow the time necessary to repair DNA damage prior to
mitosis. Parallel activation of p53 maintains the G2/M arrest over an extended
period of time. In tumor cells with dysfunctional p53, CHK1 becomes the primary
mediator of DNA damage-dependent cell cycle arrest. Since p53 signaling is
impaired in the majority of human cancers, CHK1 represents a vulnerable pathway
target to increase the effectiveness of DNA damaging chemotherapy.
CHK1 is
also an important regulator of replication origin firing. In normal cells, CHK1
stabilizes active replication forks and prevents the activation of late stage
origins until near the end of S-phase. When CHK1 activity is diminished the
number of active replication origins in the cell increases paradoxically
resulting in stalled replication forks and an increase in the duration of
S-phase.
Mechanism of Action in GDC-0425:
GDC-0425
is reported as an oral and selective small molecule inhibitor of Checkpoint
kinase 1 (CHK1). CHK1 inhibition converts a transient genotoxic insult from
chemotherapy into a cytotoxic event by overriding cell cycle arrest, allowing
cells mitosis with DNA damage.
In a reported
study GDC-0425 enhanced gemcitabine (gem) efficacy in tumor xenograft models.
Greater chemopotentiation was observed in cancer cell lines lacking p53
activity.
Dosages and Approvals:
GDC-0425
(Tradename: -) is a product that
originated and developed by Genetech. In August 2011, Array BioPharma announced
an oncology agreement with Genentech, for the development of each company's
small-molecule Checkpoint kinase 1 (CHK1) program. The programs include
Genentech's compound GDC-0425 (also known as RG7602), currently in Phase I/II,
and Array's compound ARRY-575, which is being prepared for an investigational
new drug application to initiate a Phase 1 trial in cancer patients.
Under
the terms of the agreement, Genentech is responsible for all clinical
development and commercialization activities.
Reported Activities for GDC-0425:
GDC-0425
is reported as a selective and specific inhibitor of Checkpoint kinase 1 (CHK1).
It is reported to have a better selectivity profile as compared to its
competition under Phase trials.
Summary
Common name: GDC-0425; GDC0425;
GDC 0425; RG-7602; RG7602; RG 7602
Trademarks: -
Molecular Formula: C18H19N5O
CAS Registry Number: 1200129-48-1
CAS Name: 5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile
Molecular Weight: 321.38
SMILES: CCN(CC1)CCC1OC2=C3C(NC4=C3C=CC=N4)=CN=C2C#N
InChI Key: XEZLBMHDUXSICI-UHFFFAOYSA-N
InChI: InChI=1S/C18H19N5O/c1-2-23-8-5-12(6-9-23)24-17-14(10-19)21-11-15-16(17)13-4-3-7-20-18(13)22-15/h3-4,7,11-12H,2,5-6,8-9H2,1H3,(H,20,22)
Mechanism of Action: Checkpoint Kinase 1 (CHK1)
Inhibitors; Kinase Inhibitors
Activity: Antineoplastics; Cancer Drug
Status: Under Phase Trials
Chemical Class: Small molecules; Piperidine
containing; 1,7-diazacarbazole derivatives; Nitrile containing; Cyano
containing; Ether containing; N-substituted alkyl derivatives
Originator: Genetech Pharma / Array Biopharma
