Ansamycins and derivatives | | | | | |
Geldanamycin | CRAF | Decreased protein levels | Blocks PMA-dependent ERK1/2 signaling | NIH 3T3 cells | (Schulte et al., 1997; Schulte et al., 1996) |
| | Decreased protein levels | CRAF-dependent induction of apoptosis | SH‐SY5Y cells | (Kim et al., 2003) |
| | Decreased protein levels | Inhibition of ERK1/2 signaling Cells resistant to BRAF inhibition display increased sensitivity to geldanamycin | M14 cells | (Montagut et al., 2008) |
Geldanamycin derivatives | CRAF | Decreased protein levels | N/A | SKBr3 cells | (An et al., 1997) |
17-AAG (tanespimycin) | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | Melanoma cell lines | (Joshi et al., 2018) |
| | Decreased protein levels | Inhibition of ERK1/2 signaling | Uveal melanoma cell lines | (Babchia et al., 2008) |
| | Decreased protein levels (proteasome-dependent) | Inhibition of endothelin-1–induced ERK1/2 signaling | Neonatal rat ventricular myocytes | (Tamura et al., 2019) |
| | Decreased protein levels (proteasome-dependent) Effect potentiated by combination with 7-hydroxy-staurosporine | Inhibition of ERK1/2 signaling Ectopic expression of active MEK suppresses apoptosis induced by 17-AAG and staurosporine | U937 cells | (Jia et al., 2003) |
| | Decreased protein levels | Inhibition of myocardial infarction–induced ERK1/2 activation | Rat model of coronary artery ligation | (Tamura et al., 2019) |
| | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | SK-Mel-31 and SK-Mel-28 cells in vitro and in vivo | (Grbovic et al., 2006) |
| | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | HT-29, HCT 116, and HCT 15 cells | (Hostein et al., 2001) |
| | Decreased protein in combination with trastuzumab levels (variable between patients) | N/A | Patients with HER2+ metastatic breast cancer | (Modi et al., 2007) |
| | Decreased protein levels (four of six patients) | N/A | Tumor biopsies and peripheral blood leukocytes from patients with advanced cancers | (Banerji et al., 2005) |
| | Dose-dependent decrease in protein levels (in vitro cell models) Decreased protein levels (tumor biopsies) | N/A | Ovcar3, Ovcar5, and OV17 cells Ovarian tumor biopsies | (Hendrickson et al., 2012) |
| | Decreased protein levels in combination with sorafenib (four of six patients) | Inhibition of ERK1/2 signaling | PBMCs of patients with advanced cancers | (Vaishampayan et al., 2010) |
| ARAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | SK-Mel-31 and SK-Mel-28 cells in vitro and in vivo | (Grbovic et al., 2006) |
| | Disruption of Hsp90:ARAF interaction | N/A | LUMIER assay in 293T cells | (Taipale et al., 2012) |
| BRAF (WT and V600E) | Dose-dependent decrease in BRAF V600E protein levels WT BRAF unaffected by 17-AAG, except in SK-Mel-2 cell line | Inhibition of ERK1/2 signaling 17-AAG treatment inhibits vemurafenib-induced paradoxical ERK1/2 activation in BRAF WT cells | Melanoma cell lines | (Joshi et al., 2018) |
| | Decreased protein levels | Inhibition of ERK1/2 signaling | HT-29, MCF-7, SK-MEL-28, and A2058 cells | (Fukuyo et al., 2008) |
| | Dose-dependent decrease in BRAF V600E protein levels (proteasome-dependent) BRAF WT and L597V mutant are unaffected or less sensitive to 17-AAG. Mutants V600D and G466V are sensitive to 17-AAG | Inhibition of ERK1/2 signaling | Multiple cancer cell lines: Colo829, A375, MEL-501, WM266.4, and SK-MEL-2 | (da Rocha Dias et al., 2005) |
| | Dose-dependent decrease in BRAF V600E protein levels (proteasome-dependent) Induction of ubiquitination by treatment Disruption of BRAFV600E/Hsp90 interaction | BRAF V600E mutation confers sensitivity to 17-AAG. BRAF WT is unaffected. Inhibition of ERK1/2 signaling | SK-Mel-31 and SK-Mel-28 cells in vitro and in vivo | (Grbovic et al., 2006) |
| | Dose-dependent decrease in BRAF V600E protein levels Dose-dependent decrease in WT BRAF levels (less sensitive than V600E mutant) | Inhibition of ERK1/2 signaling | Uveal melanoma cell lines | (Babchia et al., 2008) |
| | Decreased protein levels in some patients | Decreased levels of phospho-ERK1/2 in some patients | Patients with melanoma | (Solit et al., 2008) |
17DMAG | CRAF | Decreased protein levels (tumor and hepatic tissues) | N/A | MDA-MB-231 xenografts | (Eiseman et al., 2005) |
| | No consistent changes in protein levels between patients | N/A | Tumor biopsies and PBMCs of patients with advanced cancers | (Ramanathan et al., 2010) |
| BRAF (WT and V600E) | Decreased protein levels Disruption of BRAFV600E/Cdc37/Hsp90 complexes | Inhibition of ERK1/2 signaling Effects on BRAF V600E protein abundance and ERK1/2 signaling partially rescued by treatment with antioxidant N-acetylcysteine | HT-29, MCF-7, SK-MEL-28, and A2058 cells | (Fukuyo et al., 2008) |
17-ABAG | CRAF | Dose-dependent decrease in protein levels | N/A | LNCaP cells | (Lin et al., 2015) |
IPI-504 | CRAF | Decreased protein levels | Inhibition of ERK1/2 signaling | D-54MG and U-251MG cells | (Di et al., 2014) |
| | Dose-dependent decrease in protein levels | N/A | H1650 cells | (Tillotson et al., 2010) |
EC5 | CRAF | Decreased protein levels | N/A | HNSCC cell lines | (Yin et al., 2005) |
WK-88-1 | CRAF | Dose-dependent decrease in protein levels | N/A | MCF-7 and MDA-MB-231 cells | (Zhao et al., 2018) |
Herbimycin A | CRAF | Decreased protein levels | N/A | MCF-7 cells | (Schneider et al., 1996) |
Purine-based | | | | | |
PU-H71 | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | Hep3B and HuH7 cells in vitro and in vivo | (Breinig et al., 2009) |
| | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | MDA-MB-468 (in vitro and in vivo), MDA-MB-231, MCF-7, and SKBr3 cells | (Caldas-Lopes et al., 2009) |
| | Dose-dependent decrease in protein levels | N/A | MDA-MB-231 cells | (Azoitei et al., 2012) |
| | Dose-dependent decrease in protein levels | N/A | A673 cells | (Ambati et al., 2013) |
| | Dose-dependent decrease in protein levels | N/A | K562 cells | (Taldone et al., 2013) |
| | Decreased protein levels | N/A | K562 cells | (Moulick et al., 2011) |
| ARAF | Decreased protein levels | N/A | K562 cells | (Moulick et al., 2011) |
| | Disruption of Hsp90:ARAF interaction | N/A | LUMIER assay in 293T cells | (Taipale et al., 2012) |
BIIB021 | CRAF | Dose-dependent decrease in protein levels | N/A | MCF-7 cells and BT-474 breast tumor model | (Lundgren et al., 2009) |
| ARAF | Disruption of Hsp90:ARAF interaction | N/A | LUMIER assay in 293T cells | (Taipale et al., 2012) |
CUDC-305 | CRAF | Decreased protein levels | Inhibition of ERK1/2 signaling | BT-474 cells H1975, A549, and U87MG xenografts | (Bao et al., 2009a; Bao et al., 2009b) |
Radicicol and derivatives; resorcinol-based | | | | | |
Radicicol | CRAF | Decreased protein levels | Inhibition of KRAS-induced ERK1/2 signaling | KNRK5.2, PSN-1, and SKBr3 cells | (Schulte et al., 1998; Soga et al., 1998) |
| ARAF | Disruption of Hsp90:ARAF interaction | N/A | LUMIER Assay in 293T cells | (Taipale et al., 2012) |
KF25706 | CRAF | Decreased protein levels | Inhibition of KRAS-induced ERK1/2 signaling Impairment of xenograft tumor growth | KRAS-transformed rat NRK cells Human breast cancer xenografts | (Soga et al., 1999) |
KF58333 | CRAF | Decreased CRAF protein levels | Inhibition of ERK1/2 signaling | K562 cells | (Shiotsu et al., 2000) |
AT13387 (onalespib) | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling Overcoming of acquired resistance to BRAF and MEK1/2 inhibition | A375, SK-MEL-28, SK-MEL-2, SK-MEL-5, and WM266-4 cells | (Smyth et al., 2014) |
| BRAF (WT and V600E) | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling Overcoming of acquired resistance to BRAF and MEK1/2 inhibition | A375, SK-MEL-28, SK-MEL-2, SK-MEL-5, and WM266-4 cells | (Smyth et al., 2014) |
STA-9090 (ganetespib) | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling Overcoming of acquired resistance to BRAF inhibition | Melanoma cell lines | (Wu et al., 2013b) |
| | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | A375 cells | (Acquaviva et al., 2014) |
| ARAF | Disruption of Hsp90:ARAF interaction | N/A | LUMIER assay in 293T cells | (Taipale et al., 2012) |
| BRAF (WT and V600E) | Dose-dependent decrease in BRAF V600E protein levels | Inhibition of ERK1/2 signaling Overcoming of acquired resistance to BRAF inhibition | Melanoma cell lines | (Wu et al., 2013b) |
| | Dose-dependent decrease in BRAF V600E protein levels | Inhibition of ERK1/2 signaling Overcoming of intrinsic and acquired resistance to BRAF inhibition | A375 and SK-MEL-2 cell lines Primary melanocytes | (Acquaviva et al., 2014) |
NVP-AUY922 (luminespib) | CRAF | Dose-dependent decrease in protein levels | N/A | HCT 116 cells in vitro and in vivo | (Brough et al., 2008) |
| | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling Synergy with trametinib to induce apoptosis Sensitization of trametinib-resistant cells | H647 and H1944 cells in vitro and in vivo | (Park et al., 2016a) |
| | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | U87MG, SF268, SF188, and KNS42 cells | (Gaspar et al., 2010) |
| | Decreased protein levels | N/A | HCT 116 | (Eccles et al., 2008) |
| ARAF | Disruption of Hsp90:ARAF interaction | N/A | LUMIER assay in 293T cells | (Taipale et al., 2012) |
| BRAF (WT and V600E) | Decreased protein levels of BRAF V600E | Mild effect on ERK1/2 signaling Reactivation of ERK1/2 confers resistance to luminespib in BRAFV600E colon cancer cells | Lim1215, Caco-2, RKO, and WiDr cells | (Wang et al., 2016a) |
KW-2478 | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | OPM-2/GFP, NCI-H929, RPMI 8226, and U266 cells NCI-H929 xenografts | (Nakashima et al., 2010) |
CCT018159 | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | SKMEL 28 cells | (Sharp et al., 2007) |
VER-49009 | CRAF | Dose-dependent decrease in protein levels | N/A | HCT 116 cells | (Dymock et al., 2005) |
Monocillin II | CRAF | Dose-dependent decreased protein levels Reduced stability upon treatment (CHX-chase) | Inhibition of MEK/ERK signaling | MDA‐MB‐231 cells | (Wei et al., 2012) |
| ARAF | Dose-dependent decreased protein levels Reduced stability upon treatment (CHX-chase) | Inhibition of MEK/ERK signaling | MDA‐MB‐231 cells | (Wei et al., 2012) |
Benzamide scaffold | | | | | |
XL888 | CRAF | Decreased protein levels | Inhibition of ERK1/2 signaling | BRAF inhibitor–resistant melanoma cell lines | (Paraiso et al., 2012b) |
| | Decreased protein levels | Inhibition of ERK1/2 signaling XL888 inhibits vemurafenib-induced paradoxical ERK1/2 activation | NRAS mutant melanoma cells and HRAS-transformed NIH 3T3 cells | (Phadke et al., 2015a) |
| ARAF | Decreased protein levels | Inhibition of ERK1/2 signaling | BRAF inhibitor–resistant melanoma cell lines | (Paraiso et al., 2012b) |
TAS-116 | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling TAS-116 in combination with dabrafenib or AZD6244 exerts synergistic cytotoxic effects | Multiple myeloma cell lines | (Suzuki et al., 2015) |
| BRAF (WT and V600E) | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling TAS-116 treatment in combination with dabrafenib or AZD6244 exerts synergistic cytotoxic effects | Multiple myeloma cell lines | (Suzuki et al., 2015) |
N-benzyl benzamide derivatives | CRAF | Dose-dependent decrease in protein levels | N/A | H1975 cells | (Park et al., 2018) |
Novobiocin and derivatives | | | | | |
Novobiocin, chlorobiocin, and coumermycin A1 | CRAF | Dose-dependent decrease in protein levels | N/A | SKBr3 cells | (Marcu et al., 2000) |
Novobiocin and derivatives | CRAF | Decreased protein levels | N/A | MCF-7 cells | (Le Bras et al., 2007) |
Novobiocin, 4TCNA, and 7TCNA derivatives | CRAF | Decreased protein levels | N/A | Multiple cancer cell lines: Caco-2, HT-29, MDA-MB-231, IGROV1, ISHIKAWA, T47D | (Radanyi et al., 2009) |
KU135 | CRAF | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | SKMEL28 cells | (Samadi et al., 2011) |
| BRAF (WT and V600E) | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | SKMEL28 cells | (Samadi et al., 2011) |
KU363 | CRAF | Dose-dependent decrease in protein levels | N/A | MDA-1986 cells | (Cohen et al., 2012) |
Others—natural products | | | | | |
Tubocapsenolide A and others Withanolides | CRAF | Decreased protein levels | N/A | MDA-MB-231 cells | (Chen et al., 2008; Wang et al., 2012) |
Scalarane Sesterterpenoids | CRAF | Decreased protein levels | N/A | Molt 4 cells | (Lai et al., 2016) |
Other chemical classes | | | | | |
SNX-2112 | CRAF | Decreased protein levels | N/A | MCF-7 cells | (Wang et al., 2011) |
| | Dose-dependent decrease in protein levels | N/A | K562 cells | (Wang et al., 2015) |
| ARAF | Disruption of HSP90:ARAF interaction | N/A | LUMIER assay in 293T cells | (Taipale et al., 2012) |
| BRAF (WT and V600E) | Dose-dependent decrease in BRAF V600E protein levels | Inhibition of ERK1/2 signaling | A375 cells | (Liu et al., 2012b) |
| | Dose-dependent decrease in BRAF V600E protein levels | N/A | B16 cells | (Liu et al., 2012a) |
5-Aryl-3-thiophen-2-yl-1H-pyrazoles | CRAF | Decreased protein levels | N/A | HepG2 cells | (Mohamady et al., 2020) |
ITZ-1 | CRAF | Dose-dependent decrease in protein levels | Inhibition of IL-1β–induced ERK1/2 signaling | Human articular chondrocytes | (Kimura et al., 2010) |
DCZ3112 | CRAF | Dose-dependent decrease in protein levels | Cotreatment with trastuzumab inhibits ERK1/2 signaling | SK-BR-3, BT-474, and MDA-MB-231 cells in vitro and in vivo | (Chen et al., 2018) |
DCZ5248 | CRAF | Dose-dependent decrease in protein levels (proteasome-dependent) | N/A | HCT116 cells | (Chen et al., 2021) |
BDP | CRAF | Dose-dependent decrease in protein levels | N/A | MDA-MB-231 cells | (Oh and Seo, 2017) |
DPide | CRAF | Dose-dependent decrease in protein levels | N/A | MDA-MB-231 cells | (Oh et al., 2018) |
FW-04-806 | CRAF | Dose-dependent decrease in protein levels | N/A | SKBR3, MCF-7 in vitro and in vivo | (Huang et al., 2014) |
NVP-BEP800 | CRAF | Decreased protein levels | Inhibition of ERK1/2 signaling | MCF-7 and MDA-MB-231 cells | (Massey et al., 2010) |
| ARAF | Disruption of Hsp90:ARAF interaction | N/A | LUMIER assay in 293T cells | (Taipale et al., 2012) |
| BRAF (WT and V600E) | Dose-dependent decrease in protein levels | Inhibition of ERK1/2 signaling | A375 cells in vitro and in vivo | (Massey et al., 2010) |