BI-9321 for NSD3

This probe is available from Tocris, and Sigma

The probe and its negative control are also available from opnMe.com.

The control may be requested by clicking here.

For any inquiries please contact proberequests@thesgc.org.

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Overview

BI-9321

BI-9466

A collaboration between Boehringer Ingelheim and the SGC has resulted in the discovery of BI-9321, a potent and selective antagonist of the PWWP1 domain of NSD3. BI-9321 binds to the PWWP1 domain of NSD3 with a K_d of 166 nM by SPR and is selective over other PWWP domains including NSD2-PWWP1 and NSD3-PWWP2. BI-9321 antagonizes the interaction of H3 with NSD3-PWWP1 in U2OS cells as measured by NanoBRET with IC₅₀ of 1.2 µM. A closely-related compound, BI-9466 is 200-fold less active and is a recommended negative control. Both compounds should be used in parallel in a dose response range between 0.1 and 20µM.

Data relating to the discovery of this probe is being prepared for publication. In the meantime, in order to facilitate research by the community we are making this compound available through this website.

Properties

BI-9321

BI-9466
(negative control)

Physical and chemical properties for BI-9321
Molecular weight	360.2
Molecular formula	C22H21FN4
IUPAC name	4-(4-(amino-methyl)-2,6-dimethyl-phenyl)-5-(9-fluoro-2-aza-bicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-5-yl)-1-methyl-1H-imidazole
MollogP	3.337
PSA	41.44
No. of chiral centres	0
No. of rotatable bonds	3
No. of hydrogen bond acceptors	3
No. of hydrogen bond donors	2

Physical and chemical properties for BI-9466 (Negative Control)
Molecular weight	295.2
Molecular formula	C17H21N5
IUPAC name	5-(5-(4-(amino-methyl)-2,6-dimethyl-phenyl)-3-methyl-3H-imidazol-4-yl)-1-methyl-1H-imidazole
MollogP	0.7975
PSA	43.92
No. of chiral centres	0
No. of rotatable bonds	3
No. of hydrogen bond acceptors	3
No. of hydrogen bond donors	2

SMILES:
BI-9321: Cc1cc(CN)cc(C)c1c1c(c2ccnc3cc(ccc23)F)n(C)cn1
BI-9466: Cc1cc(CN)cc(C)c1c1c(c2cncn2C)n(C)cn1

InChI:
BI-9321: InChI=1S/C22H21FN4/c1-13-8-15(11-24)9-14(2)20(13)21-22(27(3)12-26-21)18-6-7-25-19-10-16(23)4-5-17(18)19/h4-10,12H,11,24H2,1-3H3

BI-9466: InChI=1S/C17H21N5/c1-11-5-13(7-18)6-12(2)15(11)16-17(22(4)10-20-16)14-8-19-9-21(14)3/h5-6,8-10H,7,18H2,1-4H3

InChIKey:
BI-9321: WOAOENGFAAUUGT-UHFFFAOYSA-N
BI-9466: SFZHMKDAVPIXRB-UHFFFAOYSA-N

Selectivity Profile

Cell-based Assay Data

Co-crystal structures

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Main features
1. Predicted binding mode with H3K36me3
2. Overlay with BI-9321 structure
3. Zoomed BI-9321 structure showing hydrogen bonds

References

Böttcher, J., Dilworth, D., Reiser, U., Neumüller, R., Schleicher, M., & Petronczki, M. et al. (2019). Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3. Nature Chemical Biology. doi: 10.1038/s41589-019-0310-x