PHGDH Inhibitor | BI-4916
Highlights
BI-4916 is an ester prodrug of the highly potent PHGDH inhibitor BI-4924. In contrast to BI-4924, BI-4916 is cell permeable, undergoing cellular uptake followed by hydrolysis to BI-4924. This allows for it to be used as intracellular enrichment of BI-4916. The negative control BI-5583 is also provided. Both compounds should be only used to perform cellular 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-4916 | BI-5583 |
| MW [Da] | 527.4 | 372.8 |
| NAD+ high assay (250 µM) (IC50) [nM]1 | 169* | n.d. |
| PHGDH SPR [µM]1 | n.a. | 28.4 |
| 13C-Serine; 72 h (IC50) [nM]1 | 2,032 | n.a. |
* The chemical stability of the tosyl acetate ester was found to be limited under the assay conditions
– It is highly likely that all activity in the biochemical assay results from the formation of the carboxylic acid analog BI-4924 which is also available on opnMe.com.
In vitro DMPK and CMC parameters
| Probe name / negative control | BI-4916 | BI-5583 |
| logP | 5.6 | n.a. |
| Solubility @ pH 6.8 [µg/ml] | <1 | >87 |
| CACO permeability @ pH 7.4 [*10-6 cm/s] | n.d. | <1.8 |
| CACO efflux ratio | n.d. | n.a. |
| Microsomal stability (human/mouse/rat) [% QH] | n.d. | 24/-/<23 |
| Hepatocyte stability (mouse) [% QH] | n.d. | n.a. |
| Plasma protein binding (10% FCS) [%] | 98.8 | Ongoing |
| CYP 3A4 (IC50) [µM] | >50 | >50 |
| CYP 2C8 (IC50) [µM] | 39.0 | >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 (@10 µM) for BI-4916, and for 3/44 proteins > 70% CTRL inhibition was found: CCKA (82%), 5HT2B (94%), ALPHA2A (101%).
| SELECTIVITY DATA AVAILABLE | BI-4916 | BI-5583 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | Yes |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-4916_selectivityData.xlsx
BI-5583_selectivityData_0.xlsx
Co-crystal structure of the BI probe compound and the target protein
BI-4924 (active form of prodrug BI-4916) bound to PHGDH (PDB code: 6RJ6)
Reference molecule(s)
Other PHGDH inhibitors have been described in literature.2
Summary
BI-4916 is the ester prodrug of BI-4924, a highly potent inhibitor of PHGDH with good selectivity. We also provide the negative control BI-5583.
The ester prodrug BI-4916 should be used to perform cellular experiments.
Supplementary data
2 D structure formats available
PHGDH inhibitor | BI-4916.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.
How to cite opnMe?
When you plan a publication, please use the following acknowledgement:
BI-4916 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://opnme.com.
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