FAS inhibitor
BI 99179
BI-99179 is a highly potent and selective non-covalent inhibitor of FAS (IC50 = 79 nM). It has significant peripheral and central exposure upon oral administration in rats, where it also showed acute efficacy. This compound may be used for in vitro and in vivo validation of FAS as a therapeutic target for lipid metabolism-related diseases.
More information
Mammalian type I fatty acid synthase (FAS) is a key enzyme for lipogenesis and highly expressed in lipogenic tissues. While most tissues, except liver and adipose tissue, have low levels of FAS expression and activity, FAS is over expressed in many cancers2, 3.
FAS inhibition could be a potential way to treat obesity4.
It has been reported that inhibitors of FAS reduce the production of sebum in sebocytes5, suggesting topical FAS inhibition as a potential anti-acne approach.
The reported involvement of FAS in the mechanisms of viral infection and replication suggests that FAS inhibition could be applied as an antiviral principle8, 9, 10.
Structure of full length fatty acid synthase, (PDB code: 2vz9.pdb).6
Human Fatty Acid Synthase Psi/KR Tri-Domain with GSK2194069 bound next to NADPH (grey; PDB code: 4piv)
The two identical subunits each comprise an acyl carrier protein (ACP) domain and six different catalytic domains.
BI 99179 most probably binds to the ketoacyl reductase domain (evidence: inhouse enzymatic data and analogy to the published co-crystal structure of the human KR domain with GSK2194069)7
BI 99179 inhibits the FAS enzyme isolated form HeLa cells with an IC50 of 79 nM. The optical antipode which can be used as a negative control shows an activity of > 3000 nM in this assay.
in vitro activity table
| Probe name / negative control | BI 99179 | BI 99990 |
| MW [Da, free base]a | 391.5 | 391.5 |
| Inhibition of FASN* (IC50) [nM]b | 79 | >3000 |
| Inhibition of [14C]acetate incorporation§ mouse N-42 cells (IC50) [nM]c | 570 | >10000 |
| Inhibition of [14C]acetate incorporation§ hum. H1975 cells (IC50) [nM]c | 180 | >10000 |
| Cytotox. (LDH release from U937 cells) (IC50) [nM]d | >30000 | n.d. |
aFor the salt form you will get, please refer to the label on the vial andn for the molecular weight of the salt, please refer to the FAQs
bHuman FAS enzyme isolated from HeLa cells
cCells incubated with compound for 1h, 14C-acetate in Krebs-Ringer-buffer incubation for 4h, Methanol:CHCl3 1:1 extraction, measurement in ß-counter;
dHEK membrane prep
| Probe name / negative control | BI 99179 | BI 99990 |
| logD @ pH 22 | 3.3 | 3.3 |
| Solubility @ pH 7 [µg/ml] | >39 | >39 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 94 | n.a. |
| Caco-2 efflux ratio | 0.9 | n.a. |
| Microsomal stability (human) [% QH] | <24 | 33 |
| CYP 3A4 (IC50) [µM] | 27.2. | n.a. |
| CYP 2C9 (IC50) [µM] | 11.9 | n.a. |
| CYP 2C19 (IC50) [µM] | 21.7 | n.a. |
| CYP 2D6 (IC50) [µM] | >50 | n.a. |
| Probe name / negative control | BI 99179 | BI 99990 |
| Clearance [mL/min/kg]a | 8.2 | n.a. |
| t1/2 [h] | 3.0 | n.a. |
| tmax [h] | 0.5 | 0.5 |
| Cmax [nM]b | 2110 | 317 |
| F [%] | 46 | n.a. |
| Vss [l/kg] | 1.6 | n.d. |
| Cbrain,2h [nM] | 1300 | n.d. |
| CCSF,2h [nM] | 50 | n.d. |
ai.v. dose: 0.4 mg/kg
bp.o. dose: 4mg/kg
BI 99179 showed acute efficacy in rats
- Increased hypothalamic [Malonyl-CoA] (10 or 100 mg/kg; 2h /24h post dose (p.d.))
![hypothalamic [Malonyl-CoA] 2h/24h p.d.](/sites/default/files/figure-5-hypothalamic.PNG)
Hypothalamic [Malonyl-CoA] 2h/24h p.d.; cbr,unbound
- Decreased cumulative food intake 100 mg/kg; 24h p.d.
Pharmacologic POC in Han Wistar rats; Food intake with refeeding after 24h fast
BI 99179 showed adverse effects beginning at day 4 (30 mg/kg), day 9 (3 mg/kg)
- Reddened and swollen mouth (not seen with 50 mg/kg BI 99990)
- Reddened and swollen eye lids (not seen with 50 mg/kg BI 99990)
- Salivation (less pronounced with BI 99990)
- Hair loss (less pronounced with BI 99990)
BI 99990 showed additional adverse effects at 50 mg/kg, therefore the compound is not suitable for further studies in rats.
BI 99990 which serves as a negative control
The optical antipode BI 99990 can be used as negative control (IC50 FAS = > 3000 nM). We tested BI 99990 also in vivo to assess if the observed adverse effects for BI 99719 are rather compound or target specific with the result that the adverse effects have not been observed or have been less pronounced with BI 99990. (For more details see in vivo pharmacology section.) BI 99990 showed additional adverse effects at 50 mg/kg, therefore the compound is not suitable for further studies in rats and should be only used in vitro.
No closely related mammalian proteins as potential off-targets.
Selectivity on non-related targets: External screen covering 30 targets: < 20% inhibition @ 10 µM for all targets. (Please see Supplementary data for detailed information)
High selectivity confirmed in > 100 in-house screens @ BI (including >10 enzymes, > 10 GPCRs, > 10 kinases, and 5 ion channels).
| SELECTIVITY DATA AVILABLE | BI 99179 | BI 99990 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| PDSP12 | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-99179_selectivityData.xlsx
BI_99990_selectivityData.xlsx
See references 3 and 11
BI 99179 is a potent and selective inhibitor for in vitro and in vivo validation of FAS as a therapeutic target for lipid metabolism related diseases.
U.S. Patent 53631
D’Arcangelis, A. D., et al.
2005
A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site
Hardwicke M. A., Rendina A. R., Williams S. P., Moore M .L., Wang L., Krueger J. A., Plant R. N., Totoritis R. D., Zhang G., Briand J., Burkhart W. A., Brown K. K., Parrish C. A.
Nature Chemical Biology 2014, 10, 774-779.
When you plan a publication, please use the following acknowledgement:
BI 99179 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.