PHGDH Inhibitor | BI-4924
Highlights
BI-4924 is a highly potent inhibitor of PHGDH. It has high selectivity against most other dehydrogenase targets and has high microsomal as well as hepatocytic stability. We also provide the cell permeable ester prodrug BI-4916, a highly selective molecule used to achieve intracellular enrichment of BI-4924. The negative control is BI-5583. These compounds are for in vitro experiments.
Background information
Target Information
PHGDH (3-phosphoglycerate dehydrogenase) catalyzes the first step of de novo serine biosynthesis downstream of glycolysis and is the rate limiting enzyme for the pathway. PHGDH converts 3-phosphoglycerate (3-PG) to 3-phosphohydroxypyruvate (3-PHP) in a NAD-dependent manner. PHGDH is amplified or overexpressed in a subset of tumors, most frequently melanoma and triple-negative breast cancers. Cells with amplified or overexpressed PHGDH show an elevated serine synthesis and are relatively resistant to serine starvation while showing some dependency on PHGDH activity.
BI-4924 bound to PHGDH (PDB code: 6RJ6)
In vitro activity
| Probe name / negative control | BI-4924 | BI-5583 |
| MW [Da] | 499.4 | 372.8 |
| NAD+ high assay (250 µM) (IC50) [nM]1 | 3 | n.d. |
| PHGDH SPR [nM]1 | 26 | 28,400 |
| 13C-Serine; 72 h (IC50) [nM]1 | 2,200 | n.a. |
In vitro DMPK and CMC parameters
To perform cellular experiments, we suggest using BI-4916 which is the ester prodrug of BI-4924 since it shows better permeability and leads to intracellular enrichment of BI-4924.
| Probe name / negative control | BI-4924 | BI-5583 |
| logP | 5.3 | n.a. |
| Solubility @ pH 6.8 [µg/ml] | 59 | >87 |
| CACO permeability @ pH 7.4 [*10-6 cm/s] | 0.21 | <1.8 |
| CACO efflux ratio | 10.8 | n.a. |
| Microsomal stability (human/mouse/rat) [% QH] | <24/<24/<23 | 24/-/<23 |
| Hepatocyte stability (mouse) [% QH] | 32 | n.a. |
| Plasma protein binding (mouse) [%] | 99.6 | Ongoing |
| CYP 3A4 (IC50) [µM] | >50 | >50 |
| CYP 2C8 (IC50) [µM] | 31 | >50 |
| CYP 2C9 (IC50) [µM] | >50 | >50 |
| CYP 2C19 (IC50) [µM] | >50 | >50 |
| CYP 2D6 (IC50) [µM] | >50 | >50 |
Negative control
BI-5583 which serves as a negative control
Selectivity
The SafetyScreen44™ panel has been measured for BI-4924, and for 2/44 proteins > 70% CTRL inhibition was found: 5HT2B (78%), PDE3A (86%).
| SELECTIVITY DATA AVAILABLE | BI-4924 | BI-5583 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | Yes |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-4924_selectivityData.xlsx
BI-5583_selectivityData.xlsx
Co-crystal structure of the BI probe compound and the target protein
BI-4924 bound to PHGDH (PDB code: 6RJ6)
Reference molecule
Other PHGDH inhibitors have been described in literature.2
Summary
BI-4924 is a potent and selective inhibitor of PHGDH. We also provide the cell permeable prodrug BI-4916 and the negative control BI-5583
Supplementary data
2 D structure formats available
PHGDH Inhibitor | BI-4924.smiles
Negative Control | BI-5583.png
References
Intracellular trapping of the selective phosphoglycerate dehydrogenase (PHGDH) inhibitor BI-4916 disrupts serine biosynthesis
Weinstabl H., Treu M., Rinnenthal J., Zahn S. K., Ettmayer P., Bader G., Dahmann G., Kessler D., Rumpel K., Mischerikow N., Savarese F., Gerstberger T., Mayer M., Zoephel A., Schnitzer R., Sommergruber W., Martinelli P., Arnhof H., Peric-Simov B., Hofbauer K. S., Garavel G., Scherbantin Y., Mitzner S., Fett T. N., Scholz G., Bruchhaus J., Burkard M., Kousek R., Ciftci T., Sharps B., Schrenk A., Harrer C., Haering D., Wolkerstorfer B., Zhang X., Lv X., Du A., Li D., Li Y., Quant J., Pearson M., McConnell D. B.
J. Med. Chem. 2019, 62, 7976–7997.
Functional Genomics Reveal that the Serine Synthesis Pathway is Essential in Breast Cancer
Possemato R., Marks K. M., Shaul Y. D., Pacold M. E., Kim D., Birsoy K., Sethumadhavan S., Woo H.-K., Jang H. G., Jha A. K., Chen W. W., Barrett F. G., Stransky N., Tsun Z.-Y., Cowley G. S., Barretina J., Kalaany N. Y., Hsu P. P., Ottina K., Chan A. M., Yuan B., Garraway L. A., Root D. E., Mino-Kenudson M., Brachtel E. F., Driggers E. M., Sabatini D. M.
Nature 2011, 476, 346.
Phosphoglycerate Dehydrogenase Diverts Glycolytic Flux and Contributes to Oncogenesis
Locasale J. W., Grassian A. R., Melman T., Lyssiotis C. A., Mattaini K. R., Bass A. J., Heffron G., Metallo C. M., Muranen T., Sharfi H., Sasaki A. T., Anastasiou D., Mullarky E., Vokes N. I., Sasaki M., Beroukhim R., Stephanopoulos G., Ligon A. H., Meyerson M., Richardson A. L., Chin L., Wagner G., Asara J. M., Brugge J. S., Cantley L. C., Vander Heiden M. G.
Nat. Genet. 2011, 43, 869.
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BI-4924 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://opnme.com.
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