SOS1 Activator | VUBI1
Highlights
VUBI1 is a potent activator of SOS1 with unique effects on the KRAS pathway. Son of Sevenless homologue 1 (SOS1) is a guanine exchange factor that acts as biological control protein for KRAS, one of the most important cellular signaling nodes. VUBI1, previously reported as compound 64,1 is a first-in-class compound that binds directly to SOS1 and agonizes its activity. BI-9930 is provided as a negative control.
Background information
Target Information
Aberrant activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) by deregulated upstream signaling, loss of GTPase-activating protein function, or oncogenic mutations results in increased GTP-bound KRAS and persistent signaling through downstream effector pathways in cancer.2,3 KRAS is the most frequently mutated oncogene in three of the deadliest cancers, as it occurs in approximately 90% of pancreatic cancer, 40% of colorectal cancer and 20% of non-small cell lung cancer cases (Data from cBioPortal TCGA Provisional accessed 2017-10-19).
RAS family small GTP/GDP binding proteins, such as KRAS, have a weak intrinsic GTPase activity and slow nucleotide exchange rates. Two classes of enzymes have evolved to facilitate cycling between the active GTP-bound state and the inactive GDP-bound form. GTPase Activating Proteins (GAPs) increase the intrinsic GTPase activity of RAS family proteins, leading to the formation of GDP bound RAS (e.g. NF1), whereas guanine nucleotide exchange factors (GEFs), such as Son of Sevenless 1 (SOS1), directly interact with KRAS and release GDP, enabling GTP binding and re-activation. Cancer-associated mutations in KRAS further suppress the intrinsic and GAP-induced GTPase activity leading to an increased population of signaling competent GTP loaded KRAS molecules.3-6
VUBI1 is a first in class potent activator of SOS1. This agonism leads directly to a rapid and dose-responsive increase in GDP-to-GTP nucleotide exchange on KRAS, which leads to higher levels of activated KRAS in cells.7 However, due to the presence of intracellular feedback mechanisms,8 a biphasic effect resulting in lower levels of activated ERK downstream of KRAS at higher doses of VUBI1 is observed. Further, decreases in phospho-AKT levels are seen.9 This compound, along with its control, offers a unique ability to activate the SOS1/KRAS axis in a controlled, reversible fashion, enabling new ways to study cellular signaling networks.
Xray crystal structure of a complex including HRAS, SOS1, and VUBI1 (PDB code: 6D55)
In vitro activity
| Probe name / negative control | VUBI1 | BI-9930 |
| MW [Da] | 483.0 | 483.0 |
| SOS1 Fluorescence Polarization Anisotropy (FPA) competition binding assay (Ki) [nM]a | 44 | > 5000 |
| HRAS Nucleotide Exchange (EC50) [nM]a | 94 | n.d. |
| p-ERK In Cell Western, HeLa cells (EC50) [nM]a | 5900 | n.d. |
| p-ERK In Cell Western, H727 cells (EC50) [nM]a | 10,000 | n.d. |
a assay conditions described in Hodges, Fesik et. al. J. Medicinal Chemistry (2018) 61, 8875-8894
In vitro DMPK and CMC parameters
| Probe name / negative control | VUBI1 | BI-9930 |
| logP logD (@ph2, 11) | n.d. | n.d. |
| Solubility @ pH 6.8 [µg/ml] | >110 | tbd |
| CACO permeability @ pH 7.4 [*10-6 cm/s] | 1.8 | 1.0 |
| CACO efflux ratio | 17.1 | 33 |
| Microsomal stability (human/mouse/rat) [% QH] | <24/<24/<23 | 33/<23/39 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 16/15/24 | 8/33/6 |
| Plasma protein binding (human/mouse/rat) [%] | 99.7/>99.8/>99.8 | 99.5/98.3/98.3 |
| hERG [inh. % @ 10 µM, 1µM] | 42.6, 7.1 | 38.2, 5 |
| hERG [IC50 (µM)] | >10 | 12.9 |
| CYP 3A4 (IC50) [µM] | 7.3 | 0.9 |
| CYP 2C8 (IC50) [µM] | 15.3 | 28.1 |
| CYP 2C9 (IC50) [µM] | 8.1 | 41.5 |
| CYP 2C19 (IC50) [µM] | >50 | >50 |
| CYP 2D6 (IC50) [µM] | >50 | >50 |
Negative control
BI-9930 is a regioisomer of VUBI1 which is inactive against SOS1 and therefore can be used as negative control.
BI-9930 which serves as a negative control
Selectivity
| SELECTIVITY DATA AVAILABLE | VUBI1 | BI-9930 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
VUBI1_selectivityData.xlsx
BI-9930_selectivityData.xlsx
Co-crystal structure of the BI probe compound and the target protein
The Xray crystal structure of a complex including HRAS, SOS1, and VUBI1 is available (PDB code: 6D55)1.
Summary
VUBI1 is a very potent Son of Sevenless homologue 1 (SOS1) agonist, which acts as a biological control protein for the KRAS pathway. Previously reported as compound 64, it binds directly to SOS1 with low double-digit nanomolar affinity. VUBI1, along with its control BI9930, offers a unique ability to activate the SOS1/KRAS axis in a controlled, reversible fashion, enabling new ways to study cellular signaling networks.
Supplementary data
References
Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS
VUBI1 is reported as compound 64: Hodges T. R., Abbott J. R., Little A. J., Sarkar D., Salovich J. M., Howes J. E., Akan D. T., Sai J., Arnold A. L., Browning C., Burns M. C., Sobolik T., Sun Q., Beesetty Y., Coker J. A., Scharn D., Stadtmueller H., Rossanese O. W., Phan J., Waterson A. G., McConnell D. B., Fesik S. W.
J. Med. Chem. 2018, 61, 8875-8894.
Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling
Abbott J. R., Hodges T. R., Daniels R. N., Patel P. A., Kennedy J. P., Howes J. E., Akan D. T., Burns M. C., Sai J., Sobolik T., Beesetty Y., Lee T., Rossanese O. W., Phan J., Waterson A. G., Fesik S. W.
J. Med. Chem. 2018, 61(14), 6002-6017.
How to cite opnMe?
When you plan a publication, please use the following acknowledgement:
VUBI1 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://opnme.com.
