AbstractThe surface of ultrasmall gold nanoparticles with an average diameter of 1.55 nm was conjugated with a 14‐3‐3 protein‐binding peptide derived from CRaf. Each particle carries 18 CRaf peptides, leading to an overall stoichiometry of Au(115)Craf(18). The binding to the protein 14‐3‐3 was probed by isothermal titration calorimetry (ITC) and fluorescence polarization spectroscopy (FP). The dissociation constant (KD) was measured as 5.0 μM by ITC and 0.9 μM by FP, which was close to the affinity of dissolved CRaf to 14‐3‐3σ. In contrast to dissolved CRaf, which alone did not enter HeLa cells, CRAF‐conjugated gold nanoparticles were well taken up by HeLa cells, opening the opportunity to target the protein inside a cell.

01 Feb 2016·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Discovery of highly selective CRAF inhibitors, 3-carboxamido-2H-indazole-6-arylamide: In silico FBLD design, synthesis and evaluation

Q4 · MEDICINE

Article

Author: Aman, Waqar ; Hah, Jung-Mi ; Lee, Junghun ; Kim, Minjung ; Jung, Hoyong ; Yang, Songyi

The recent success of vemurafenib shows the importance of selective BRAF V600E inhibition in melanoma. However, paradoxical activation by structurally diverse ATP-competitive RAF kinase inhibitors strongly suggests that selective CRAF inhibitors, not BRAF inhibitors, would be ideal for some Ras mutation cancer treatment. In this respect, we approached designing selective CRAF inhibitors starting from in silico fragment screening and synthesized a 3-carboxamido-2H-indazole-6-arylamide scaffold. Most of the compounds showed potent antiproliferative activity against the WM3629 melanoma cell line and the most promising compound, compound 10d, was found to be a potent and selective CRAF inhibitor with an IC50 value of 38.6 nM, which shows greater than 270-fold selectivity over BRAF kinase (9.45 μM).

01 Jun 2013·Molecular Cancer TherapeuticsQ2 · MEDICINE

Inhibition of Wee1, AKT, and CDK4 Underlies the Efficacy of the HSP90 Inhibitor XL888 in an In Vivo Model of NRAS-Mutant Melanoma

Q2 · MEDICINE

Article

Author: Wood, Elizabeth ; Koomen, John M. ; Rebecca, Vito W. ; Smalley, Keiran S.M. ; Haarberg, H. Eirik ; Paraiso, Kim H.T. ; Sondak, Vernon K.

AbstractThe HSP90 inhibitor XL888 is effective at reversing BRAF inhibitor resistance in melanoma, including that mediated through acquired NRAS mutations. The present study has investigated the mechanism of action of XL888 in NRAS-mutant melanoma. Treatment of NRAS-mutant melanoma cell lines with XL888 led to an inhibition of growth, G2–M phase cell-cycle arrest, and the inhibition of cell survival in three-dimensional spheroid and colony formation assays. In vitro, HSP90 inhibition led to the degradation of ARAF, CRAF, Wee1, Chk1, and cdc2 and was associated with decreased mitogen-activated protein kinase (MAPK), AKT, mTOR, and c-jun NH2 kinase (JNK) signaling. Apoptosis induction was associated with increased BIM expression and a decrease in the expression of the prosurvival protein Mcl-1. The critical role of increased BIM and decreased Mcl-1 expression in the survival of NRAS-mutant melanoma cell lines was shown through siRNA knockdown and overexpression studies. In an animal xenograft model of NRAS-mutant melanoma, XL888 treatment led to reduced tumor growth and apoptosis induction. Important differences in the pattern of client degradation were noted between the in vivo and in vitro studies. In vivo, XL888 treatment led to degradation of CDK4 and Wee1 and the inhibition of AKT/S6 signaling with little or no effect observed upon ARAF, CRAF, or MAPK. Blockade of Wee1, using either siRNA knockdown or the inhibitor MK1775, was associated with significant levels of growth inhibition and apoptosis induction. Together, these studies have identified Wee1 as a key target of XL888, suggesting novel therapeutic strategies for NRAS-mutant melanoma. Mol Cancer Ther; 12(6); 901–12. ©2013 AACR.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	US	Plexium, Inc.Startup	05 Jan 2024

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