Thursday, November 10, 2016

Drugs in Clinical Pipeline: GDC-0425 | Kinase Inhibitors | Checkpoint Kinase (CHK1) Inhibitor | Cancer Drug

GDC-0425 [5-((1-ethylpiperidin-4-yl)oxy)-9H-pyrrolo[2,3-b:5,4-c']dipyridine-6-carbonitrile] is an orally bio-available small molecule inhibitor of checkpoint kinase 1 (CHK1) that has been developed as a treatment for various cancerous malignancies. Chemically, it is a 6-cyano bearing 1,7-diazacarbazole derivative, which resulted from optimization of a 2-aminoazine series for  CHK1 activity.

Structure of GDC-0425
GDC-0425: 2D and 3D Structure

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.


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
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
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