Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	75	24	2015 Dec 15	5211-8	Cancer Res

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
SBI-0640726	SBI-0640726	2
SBI-0640756	SBI-0640756	3
SBI-755199	SBI-755199	1

Drug Name	Synonyms	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
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
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-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
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	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
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
CDKN2A loss NRAS Q61K	melanoma	sensitive	SBI-0640756	Preclinical	Actionable	In a preclinical study, SBI-0640756 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-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
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