[ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors.]
>>IDrugs. 2010 Jun;13(6):404-14.
ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors.
Bagai R, Fan W, Ma PC.
Case Western Reserve University, Ireland Cancer Center, University Hospitals Case Medical Center, Division of Hematology/Oncology, Department of Medicine, 10900 Euclid Avenue, WRB 2-123, Cleveland, OH 44106, USA. patrick.ma@case.edu.
Abstract
ARQ-197 is an oral, selective c-Met inhibitor under development by ArQule Inc, in partnership with Daiichi Sankyo Co Ltd and Asian licensee Kyowa Hakko Kirin Co Ltd, for the potential treatment of solid tumors, including NSCLC, hepatocellular carcinoma and pancreatic cancer, as well as microphthalmia transcription factor-driven tumors. c-Met, a key cell surface receptor tyrosine kinase involved in diverse regulatory functions, is often aberrantly activated in human cancers. While the precise mechanism of action of ARQ-197 remains undefined, data from preclinical studies have demonstrated that ARQ-197 inhibits c-Met activation in numerous human tumor cell lines and specifically targets c-Met in various cancer types; uniquely, ARQ-197 inhibits c-Met in a non-ATP-competitive manner. Phase I/II clinical trials demonstrated promise in terms of both tolerability and tumor response. Intriguingly, dose-limiting adverse effects were hematological in nature. Combinational trials are also ongoing to take advantage of the signaling crosstalk between c-Met and other oncogenic signaling systems. Prioritization of the clinical development of c-Met inhibitors, such as ARQ-197, among different tumor disease types is a key challenge at present; an improved understanding of the prediction of molecular determinants in tumors with respect to c-Met kinase as the driver oncogenic receptor, and of the prediction of tumor response, is still urgently needed.<<
Ah yes, the crosstalk thingie. It seems to be involved with both PI3K and MAPK pathways. Want to see complicated?
en.wikipedia.org
from
en.wikipedia.org
Anyhow, what jumped out at me in this abstract was the phrase "uniquely, ARQ-197 inhibits c-Met in a non-ATP-competitive manner." Any idea why this is significant? I gather this means it does not mess with the c-MET binding site for ATP, but I do not understand the advantage of this. I thought the whole idea was to stop the ATP binding, because that stops phosphorylation and thus recruitment of downstream effectors in the pathway; i.e. inhibits in this manner. 197 inhibits in some unknown manner, and they seem to be implying it is better?
Also, DLTs were hematological in nature? Really? Looking back at the final P1 results, I do see neutropenia as a DLT, but only one instance, along with mucositis, fatigue, and hand and foot syndrome, niether of which seem very hematological to me. But I gather the idea is that since the MOA and AEs are different, that makes it easier for combo therapy.
asco.org
TIA & Cheers, Tuck (re CRXL: watching, but know nothing) |
