Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search
Abstract
:1. Introduction
2. Results and Discussions
2.1. Scaffold Hopping- and Similarity-Based Virtual Screening
2.2. AlphaLISA-Based Biological Tests
2.3. Validation of DC-S285′s Activity
2.4. Cellular Activity of DC-S285
2.5. Similarity-Based Analog Searching and SAR Analysis
2.6. Selectivity of DC-S303
2.7. Binding Mode Prediction of DC-S303
3. Materials and Methods
3.1. Virtual Screening: Ligand Database Preparation
3.2. Virtual Screening: ProteinPreparation
3.3. Virtual Screening: 2D Molecular FingerprintBased Similarity Search
3.4. Virtual Screening: Scaffold Hopping Based Similarity Search
3.5. SET7 Inhibition Assays
3.6. Enzymatic Selectivity Assays
3.7. NMR Experiment
3.8. Cell Culture and Cell Viability Assay
4. Conclusions
Acknowledgments
Author Contribution
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Substrates | Functions | References | |
---|---|---|---|
Histone | H3K4 | transcriptional activation | [27,28] |
H2A | [29] | ||
H2BK15 | [29] | ||
H1.4 | [30] | ||
Non-histone | ARTD1 | stimulating poly-ADP-ribose formation after oxidative stress | [31] |
COL2A1 | morphology-dependent COL2A1 gene transactivation | [32] | |
DNMT1 | protein stability regulation of DNMT1 (destabilization) | [33,34] | |
E2F1 | regulation of E2F1 stabilization co-activator in response to DNA damage | [35,36] | |
ERα | protein stability regulation of ERα (stabilization) and enhancing transcriptional activity | [20,37] | |
FoxO3 | protein stability regulation of FoxO3 (destabilization) | [38] | |
FXR | transcriptional activation of FXR-target genes | [39] | |
GATA1 | required for GATA1-induced breast tumour angiogenesis and growth in nude mice; poor prognostic factors in breast cancer | [40] | |
Gli3 | activation of Sonic Hedgehog pathway in mammals | [41] | |
HIF-1α | promoting HIF-1α protein stability in hypoxia and enhancing HIF-1 mediated glycolytic gene transcription | [21] | |
HIF-1α/2α | negatively regulation HIF-α transcriptional activity and HIF-1-mediated glucose homeostasis | [42,43] | |
IFITM3 | negatively affected IFITM3 antiviral activity | [44] | |
MCP-1 | regulation of MCP-1 mRNA expression | [45] | |
MYPT1 | protein stability regulation of MYPT1 (stabilization) | [23] | |
p21 | [46] | ||
p53 | |||
p65 (RelA) | regulation of NF-κB activity | [11,47,48] | |
PCAF | [49] | ||
PDX1 | maintenance of Pdx1 activity and β cell function; control insulin gene expression based on glucose concentration | [50,51,52] | |
PCG-1α | [53] | ||
pRb | cell cycle arrest | [13,14] | |
RARα | [54] | ||
RB | promotes cell cycle progression | [55] | |
NFE2L2 | negatively regulates the expression of NFE2L2 and its downstream genes | [56] | |
Smad7 | [57,58] | ||
SIRT1 | inducing the dissociation of SIRT1 from p53 and increasing p52 activity | [59] | |
STAT3 | negatively regulation of protein stability and transactivation activity | [22] | |
SUV39H1 | gene instability and cell proliferation inhibition | [12,60] | |
TAF7 | RNA polymerase ii-dependent transcription coactivator | [61] | |
TAF10 | RNA polymerase ii-dependent transcription coactivator | [62] | |
TAT | enhancing HIV transcription | [63] | |
TGF-β1 | transcriptional activation of fibrotic genes | [64,65] | |
TP2 | elongating to condensing spermatids | [66] | |
YAP | control YAP subcellular localization and function | [67] | |
YY1 | regulation of YY1 DNA-binding activity | [68] | |
AKA6 | unknown | [29] | |
CENPC | unknown | [29] | |
MeCP2 | unknown | [29] | |
MINT | unknown | [29] | |
PPARBP, | unknown | [29] | |
ZDH8 | unknown | [29] | |
Cullin1 | unknown | [29] | |
IRF1/2 | unknown | [29] |
No. | R1 | R2 | R3 | Inhibition Ratio at 100 μM/% | IC50 (μM) |
---|---|---|---|---|---|
DC-S303 | (A) | 99 | 1.1 | ||
DC-S304 | 44 | ||||
DC-S305 | −5 | ||||
DC-S306 | 94 | 20 | |||
DC-S307 | 8 | ||||
DC-S308 | 7 | ||||
DC-S309 | −5 | ||||
DC-S310 | −6 | ||||
DC-S311 | 97 | 13 | |||
DC-S312 | −3 | ||||
DC-S313 | −6 | ||||
DC-S314 | (B) | 77 | 46 | ||
DC-S315 | 46 | ||||
DC-S316 | 37 | ||||
DC-S317 | 29 | ||||
DC-S318 | 17 | ||||
DC-S319 | 14 | ||||
DC-S320 | 11 | ||||
DC-S321 | 9 | ||||
DC-S334 | (C) | 96 | 9.9 | ||
DC-S335 | 12 | IC50 (μM) | |||
DC-S336 | 49 | 1.1 | |||
DC-S337 | 1 | ||||
DC-S338 | 1 | ||||
DC-S339 | −6 | 20 | |||
DC-S340 | −6 | ||||
DC-S341 | −10 | ||||
DC-S342 | −13 | ||||
DC-S343 | (D) | 1 | |||
DC-S344 | 32 | 13 | |||
DC-S345 | 29 | ||||
DC-S346 | 21 | ||||
DC-S347 | 10 | ||||
DC-S348 | −11 | ||||
DC-S349 | −1 | ||||
DC-S350 | 6 | ||||
DC-S351 | 96 | 3.4 | |||
DC-S352 | 39 | ||||
DC-S353 | 35 | ||||
DC-S354 | 35 | ||||
DC-S355 | 20 | ||||
DC-S356 | 17 | ||||
DC-S357 | 13 | ||||
DC-S358 | 6 | ||||
DC-S359 | 5 | ||||
DC-S360 | 4 | ||||
DC-S361 | −1 | ||||
DC-S362 | −4 | ||||
DC-S363 | −15 | ||||
DC-S364 | 54 | 3.7 | |||
DC-S365 | (E) | 10 | |||
DC-S366 | 9 | ||||
DC-S367 | −1 |
Compound No. | Target | Inhibition Ratio at 100 μM/% |
---|---|---|
DC-S303 | SETD7 | 90.51 |
SETD1B | 27.12 | |
SETD8 | 55.23 | |
G9a | 52.56 | |
SMYD2 | 24.55 | |
EZH2 | 47.88 |
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Share and Cite
Ding, H.; Lu, W.C.; Hu, J.C.; Liu, Y.-C.; Zhang, C.H.; Lian, F.L.; Zhang, N.X.; Meng, F.W.; Luo, C.; Chen, K.X. Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search. Molecules 2018, 23, 567. https://doi.org/10.3390/molecules23030567
Ding H, Lu WC, Hu JC, Liu Y-C, Zhang CH, Lian FL, Zhang NX, Meng FW, Luo C, Chen KX. Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search. Molecules. 2018; 23(3):567. https://doi.org/10.3390/molecules23030567
Chicago/Turabian StyleDing, Hong, Wen Chao Lu, Jun Chi Hu, Yu-Chih Liu, Chen Hua Zhang, Fu Lin Lian, Nai Xia Zhang, Fan Wang Meng, Cheng Luo, and Kai Xian Chen. 2018. "Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search" Molecules 23, no. 3: 567. https://doi.org/10.3390/molecules23030567