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Ref Type Journal Article
PMID (26603897)
Authors Feng Y, Pinkerton AB, Hulea L, Zhang T, Davies MA, Grotegut S, Cheli Y, Yin H, Lau E, Kim H, De SK, Barile E, Pellecchia M, Bosenberg M, Li JL, James B, Hassig CA, Brown KM, Topisirovic I, Ronai ZA
Title SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex.
Journal Cancer research
Vol 75
Issue 24
Date 2015 Dec 15
URL
Abstract Text Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF, and NF1-mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Furthermore, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAF-independent and BRAFi-resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SBI-0640726 SBI-0640726 2 0
SBI-0640756 SBI-0640756 3 0
SBI-755199 SBI-755199 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SBI-0640726 SBI-726 SBI-0640726, a structural analog of the eIF4F complex inhibitor SBI-0640756, inhibits Akt/mTOR signaling in cells in culture (PMID: 26603897).
SBI-0640756 SBI-756 SBI-0640756 inhibits the eIF4F complex, thereby inhibiting mRNA translation as well as inhibition of Akt/mTOR signaling (PMID: 26603897).
SBI-755199 SBI-755199, a structural analog of the eIF4F complex inhibitor SBI-0640756, inhibits mRNA initiation and induces cell death in human cancer cell lines (PMID: 26603897).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS mutant melanoma sensitive SBI-0640756 Preclinical Actionable In a preclinical study, SBI-0640756 inhibited proliferation and transformation of human melanoma cell lines harboring NRAS mutation in culture (PMID: 26603897). 26603897
BRAF V600E melanoma sensitive SBI-755199 Preclinical Actionable In a preclinical study, SBI-755199 induced cell death in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26603897). 26603897
BRAF V600E melanoma sensitive SBI-0640726 Preclinical Actionable In a preclinical study, SBI-0640726 inhibited proliferation and Akt/mTOR signaling in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26603897, PMID: 20531415). 20531415 26603897
NRAS mutant melanoma sensitive BI-69A11 Preclinical Actionable In a preclinical study, BI-69A11 inhibited proliferation and transformation of human melanoma cell lines harboring NRAS mutation in culture (PMID: 26603897). 26603897
BRAF V600E melanoma sensitive SBI-0640756 + Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Zelboraf (vemurafenib) in combination with SBI-0640756 inhibited the association of eIF4G1 and eIF4E in Zelboraf (vemurafenib) resistant human melanoma cell lines harboring BRAF V600E in culture and reduced tumor growth in xenograft models (PMID: 26603897). 26603897
CDKN2A loss NRAS Q61K melanoma sensitive SBI-0640756 Preclinical Actionable In a preclinical study, SBI-0640726 delayed tumor growth of melanomas in mice with a genetic background of NRAS Q61K and CDKN2A loss (PMID: 26603897). 26603897
BRAF V600E melanoma sensitive SBI-0640756 Preclinical Actionable In a preclinical study, SBI-0640756 inhibited proliferation and Akt/mTOR signaling in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26603897, PMID: 20531415). 20531415 26603897
NRAS mutant melanoma sensitive SBI-0640726 Preclinical Actionable In a preclinical study, SBI-0640726 inhibited proliferation and transformation of human melanoma cell lines harboring NRAS mutation in culture (PMID: 26603897). 26603897
BRAF V600E melanoma sensitive BI-69A11 Preclinical Actionable In a preclinical study, BI-69A11 inhibited proliferation and Akt/mTOR signaling in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26603897, PMID: 20531415). 20531415 26603897