Thursday, August 13, 2015

Drugs in Clinical Pipeline: SGX523

SGX523 [6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo-[4,3-b]pyridazin-3-ylsulfanyl] quinoline] is an orally bio-available, ATP competitive, small molecule inhibitor of MET, binding the kinase domain active site in a novel mode. 

SGX523 potently inhibited MET with an IC50 of 4 nM and is greater than 1000-fold selective versus more than 200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity [1]. SGX523 is therefore ideally suited to understand the role of MET catalytic activity in tumorigenesis without the confounding effects of off-target kinase inhibition.

SGX523 showed ATP-competitive inhibition with higher apparent affinity for the less active, unphosphorylated form of MET (Ki = 2.7 nM) versus the more active phospho-enzyme (Ki = 23 nM), a phenomenon consistent with preferential binding to an inactive enzyme conformation. Enzymatic studies showed that SGX523 potently inhibits the purified MET catalytic domain but not the closely related receptor tyrosine kinase RON. The kinase selectivity profile of SGX523 was assayed against 213 protein kinases, including wild-type and mutant (Met1268Thr) MET. In this assay, SGX523 inhibits wild-type MET with an IC50 of 4 nM. At a screening concentration of 1 uM, no protein kinase from the panel, other than MET or METMet1268Thr, was inhibited by greater than 36%. Formal IC50 determinations were conducted for the five most sensitive kinases (BRAF, ABL, RAF1, MAPK14, ABL1Y253F). No significant enzyme inhibition was observed, even at compound concentrations from 7 uM and more [1].

The activity of SGX523 is as follows:

IC50 (MET enzyme assay) = 4 nM

Common Name: SGX523
Synonyms: SGX-523; SGX523; SGX523
IUPAC Name: 6-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)thio) quinoline
CAS Number: 1022150-57-7
Mechanism of Action: Kinase Inhibitor; MET Kinase Inhibitor
Indication: Various Cancers; Solid Tumors
Development Stage: Phase I. Drug development has been stopped.
Company: SGX Pharmaceuticals

Hepatocyte growth factor (HGF) receptor, c-Met, or MET, is the prototypic member of a family of receptor tyrosine kinases unique to deuterostomes. MET orchestrates the complex program of branching morphogenesis, which is critical during embryonic development and tissue repair and for invasive growth in cancer. Activating point mutations in the MET gene are found in hereditary and sporadic forms of papillary renal carcinoma and gene amplification leads to upregulated MET signaling in other tumors, notably in the context of acquired resistance to epidermal growth factor receptor inhibitors in lung cancer. In other malignancies, such as glioblastoma, autocrine activation of MET by HGF has been shown, and MET inhibition is effective in mouse models of glioblastoma.

Phase I Study [3]


Two phase 1, open-label, dose-escalation studies of SGX523 were conducted to evaluate both interrupted and continuous dosing schedules. Thirty-six patients per study were planned to be enrolled. The first study explored a 21-day cycle with SGX523 administered on an intermittent schedule at a starting dose of 60 mg PO BID for 14 days followed by 7 days of rest. The second protocol explored a continuous 28-day dosing schedule with SGX523 administered at a starting dose of 20 mg PO BID for 28 days without rest.


A total of 10 patients were enrolled, 2 on the intermittent dosing protocol and 8 on the continuous dosing protocol. All 6 patients that received daily doses of = 80 mg developed unexpected renal failure manifested by an early rise of serum blood urea nitrogen and creatinine. Human PK analysis revealed the formation of two insoluble metabolites at levels not seen in the rat or dog preclinical toxicology studies. Subsequent primate toxicology and toxicokinetic evaluation replicated human findings, and histological examination of the monkey kidneys revealed the formation of crystals both within the renal tubules and within giant cell macrophages.


Primate toxicology studies suggest the cause of the renal failure seen in humans was a crystal nephropathy secondary to insoluble metabolites. SGX523 is no longer in clinical development.

1. Buchanan, S. G.; et. al. SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther 2009, 8(12), 3181-3190.
2. Safety Study of SGX523, a Small Molecule Met Inhibitor, to Treat Solid Tumors. NCT00607399 (retrieved 01-08-2015)
3. Infante, J. R.; et. al. Unexpected renal toxicity associated with SGX523, a small molecule inhibitor of MET. Invest New Drugs 2013, 31(2), 363-369.