Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation

Venukadasula, Phanindra K. M.; Owusu, Benjamin Y.; Bansal, Namita; Ross, L. J. N.; Hobrath, Judith V.; Bao, Donghui; Truss, Jackie W.; Stackhouse, Murray; Messick, Troy E.; Klampfer, Lidija; Galemmo, Robert A.

doi:10.1021/acsmedchemlett.5b00357

Cited by 21 publications

(18 citation statements)

References 27 publications

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“…The design of SRI 31215 (Figure 1A ) was based upon a structural template adapted from inhibitors of clotting factor Xa [ 44 , 45 ]. Details of the structure-based design effort have been reported elsewhere [ 46 ]. We demonstrated that SRI 31215 is an equipotent inhibitor of matriptase (IC 50 = 0.69 μM), hepsin (IC 50 = 0.65 μM) and HGFA (IC 50 = 0.3 μM) (Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…We demonstrated that SRI 31215 is an equipotent inhibitor of matriptase (IC 50 = 0.69 μM), hepsin (IC 50 = 0.65 μM) and HGFA (IC 50 = 0.3 μM) (Figure 1A ). While the selectivity of SRI 31215 for trypsin and thrombin is acceptable, currently we are optimizing its selectivity over factor Xa [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

“…While SRI 31215 did not interfere with scattering induced by active HGF, it prevented fibroblast-induced cell scattering as effectively as the kinase inhibitor JNJ 38877605 (Figure 2B ). SRI 31215 blocked scattering of cancer cells in a dose-dependent manner with biological activity detected at 1μM [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

et al. 2016

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The binding of hepatocyte growth factor (HGF) to its receptor MET activates a signaling cascade that promotes cell survival, proliferation, cell scattering, migration and invasion of malignant cells. HGF is secreted by cancer cells or by tumor-associated fibroblasts as pro-HGF, an inactive precursor. A key step in the regulation of HGF/MET signaling is proteolytic processing of pro-HGF to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA).We developed SRI 31215, a small molecule that acts as a triplex inhibitor of matriptase, hepsin and HGFA and mimics the activity of HAI-1/2, endogenous inhibitors of HGF activation. We demonstrated that SRI 31215 inhibits fibroblast-induced MET activation, epithelial-mesenchymal transition and migration of cancer cells. SRI 31215 overcomes primary resistance to cetuximab and gefitinib in HGF-producing colon cancer cells and prevents fibroblast-mediated resistance to EGFR inhibitors. Thus, SRI 31215 blocks signaling between cancer cells and fibroblasts and inhibits the tumor-promoting activity of cancer-associated fibroblasts.Aberrant HGF/MET signaling supports cell survival, proliferation, angiogenesis, invasion and metastatic spread of cancer cells, establishing HGF and MET as valid therapeutic targets. Our data demonstrate that inhibitors of HGF activation, such as SRI 31215, merit investigation as potential therapeutics in tumors that are addicted to HGF/MET signaling. The findings reported here also indicate that inhibitors of HGF activation overcome primary and acquired resistance to anti-EGFR therapy, providing a rationale for concurrent inhibition of EGFR and HGF to prevent therapeutic resistance and to improve the outcome of cancer patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

et al. 2016

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“…The HGF-MET cascade is considered a key target for inhibiting cancer metastasis (Mizuno and Nakamura, 2013). The proteolytic conversion of pro-HGF to active HGF is the rate-limiting step in this signaling cascade (Venukadasula et al, 2015) and, therefore, is a primary target on current approaches to preventing HGF/MET signaling.…”

Section: Introductionmentioning

confidence: 99%

“…HAI-1 and HAI-2 are synthesized as type-1 transmembrane glycoproteins and both have two Kunitz-type serine protease domains, the first of which is thought to be responsible for the HGFAinhibitory activity (Berger, 2002;Parr et al, 2004). The balance between these inhibitors and serine proteases is a critical factor in HGF activation in tumors (Parr and Jiang, 2006;Venukadasula et al, 2015). HAI-1 is a suggested marker of prostate epithelial cell proliferation (Warren et al, 2009), and a favorable prognostic marker of prostate cancer (Nagakawa et al, 2006;Yasuda et al, 2013;Hu et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

KLK14 interactions with HAI‐1 and HAI‐2 serine protease inhibitors: A molecular dynamics and relative free‐energy calculations study

Solís-Calero

Carvalho

2017

Cell Biology International

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Kallikrein 14 (KLK14) is a serine protease linked to several pathologies including prostate cancer and positively correlates with Gleason score. Though KLK14 functioning in cancer is poorly understood, it has been implicated in HGF/Met signaling, given that KLK14 proteolytically inhibits HGF activator-inhibitor 1 (HAI-1), which strongly inhibits pro-HGF activators, thereby contributing to tumor progression. In this work, KLK14 binding to either hepatocyte growth factor activator inhibitor type-1 (HAI-1) or type-2 (HAI-2) was essayed using homology modeling, molecular dynamic simulations and free-energy calculations through MM/PBSA and MM/GBSA. KLK14 was successfully modeled. Calculated free energies suggested higher binding affinity for the KLK14/HAI-1 interaction than for KLK14/HAI-2. This difference in binding affinity is largely explained by the higher stability of the hydrogen-bond networks in KLK14/HAI-1 along the simulation trajectory. A key arginine residue in both HAI-1 and HAI-2 is responsible for their interaction with the S1 pocket in KLK14. Additionally, MM/GBSA free-energy decomposition postulates that KLK14 Asp174 and Trp196 are hotspots for binding HAI-1 and HAI-2.

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Discovery and Function of theHGF/METand theMSP/RONKinase Signaling Pathways in Cancer

Benvenuti

Milan

Comoglio

2018

Extracellular Targeting of Cell Signaling in Cancer

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Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation

Cited by 21 publications

References 27 publications

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling

KLK14 interactions with HAI‐1 and HAI‐2 serine protease inhibitors: A molecular dynamics and relative free‐energy calculations study

Discovery and Function of theHGF/METand theMSP/RONKinase Signaling Pathways in Cancer

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