SOS1::KRAS PPI inhibitor | BI-3406

Target protein: 
SOS1::KRAS
BI-3406

Information

Call for collaboration proposals

With our orally bioavailable SOS1::KRAS antagonist BI-3406 we share an unprecedented, highly potent and selective protein-protein interaction inhibitor for collaboration. Interested scientists from around the world are invited to submit testable research proposals with this molecule around novel disease indications.

All incoming proposals will be evaluated by a scientific jury, and, upon selection, chosen proposals are pursued through a joint collaboration with the successful applicants. Funding of up to 200.000 Euro will be available for each selected proposal.

We can only accept research proposals if they arrive by the submission deadline on December 13, 2019 23.59 pm PST.

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Target information

Aberrant activation of KRAS by deregulated upstream signaling, loss of GTPase-activating protein function, or oncogenic mutations results in increased GTP-bound KRAS and persistent signaling1,2. KRAS is the most frequently mutated oncogene in three of the deadliest cancers, as it occurs in ~90% of pancreatic cancer, ~40% of colorectal cancer and ~30% of non-small cell lung cancer cases (Data from cBioPortal TCGA).

Besides KRAS mutations or amplifications several other aberrations in GTPase activating proteins (e.g. NF1) are known. Hence, the pathway plays a significant role in other indications outside oncology as well (e.g. RASopathies).

Our compound BI-3406 inhibits the protein interaction between Son of Sevenless 1 (SOS1) and Kirsten rat sarcoma viral oncogene (KRAS) leading to a disruption of downstream signaling. The binding occurs at the catalytic site of SOS1, inhibiting the interaction with RAS‐GDP. This significantly reduces formation of activated, GTP-bound KRAS and thereby inhibits downstream MAPK signaling.
Our SOS1::KRAS inhibitor is proven to be active in KRAS addicted cell lines in vitro using 3D proliferation assays as well in vivo in KRAS mutant mouse models [data on file]. The compound will be provided free of charge in the amount required for the experiments.

In Vitro Activity

The novel, non-covalent and orally bioavailable small molecule BI-3406 inhibits the interaction of SOS1 with GDP-loaded KRAS with an IC50 of 5 nM. In KRAS mutant NCI-H358 cells the small molecule SOS1::KRAS inhibitor reduces pERK formation with an IC50 of 4 nM and cellular proliferation with an IC50 of 24 nM in 3D assays. The inhibitor does not display any species selectivity versus mouse KRAS mutant cell lines. The SOS1::KRAS inhibitor was also shown to be selective versus SOS2 (IC50 > 10 µM) and to be selective in a panel of 324 kinases (no off-target hits at 5 µM).

Assay

IC50 [nM]

SOS1 IC50 (GDP-loaded KRAS)

5

SOS2 IC50

>10000

pERK formation IC50 (KRAS mutant NCI-H358 cells)

4

Inhibition of cellular proliferation IC50 (KRAS mutant NCI-H358 cells)

24

In vitro DMPK parameters

Our oral small molecule SOS1::KRAS inhibitor has good solubility in water at all pH values. It showed high permeability in Caco2 assay but significant efflux in the MDCK permeability assay.

In vivo DMPK parameters

Pharmacokinetic (PK) properties in rodent animal species are suitable for once or twice daily oral dosing in acute or sub-chronic in vivo experiments. In KRAS mutant MIA-PaCa-2 twice daily oral treatment with our small molecule SOS1::KRAS inhibitor results in a tumor growth inhibition of ~60-90%. The oral SOS1::KRAS inhibitor is suitable for oral in vivo testing in rodent species and is expected to have low brain exposure.

Selectivity

The SOS1::KRAS inhibitor was shown to be selective versus SOS2 (IC50 > 10 µM) and to be selective in a panel of 324 kinases (no off-target hits at 5 µM).

Supplementary data

The shared oral SOS1::KRAS inhibitor is a member of a family of compounds generated in our SOS1::KRAS inhibitor program. Additional compounds have different properties and pharmacological profiles and may also be available for sharing.

Summary

With our oral SOS1::KRAS inhibitor BI-3406 we share an unprecedented, highly potent and selective molecule for collaboration. It inhibits the protein-protein interaction of SOS1 with KRAS-GDP this way preventing the exchange to activated KRAS-GTP. Interested scientists from around the world are now invited to submit testable research proposals with our oral SOS1::KRAS inhibitor around novel disease indications.

All incoming proposals will be evaluated by a scientific jury, and, upon selection, chosen proposals are pursued through a joint collaboration with the successful applicant. Funding of up to 200.000 Euro will be available for each selected proposal.

We can only accept research proposals if they arrive by the submission deadline on December 13, 2019 23.59 pm PST.

References

  1. Drugging the undruggable RAS: Mission possible?

    Cox A. D., Fesik S. W., Kimmelman A. C., Luo J., Der C. J.

    Nat Rev. Drug. Discov. 2014, 13 (11) 828-851

  2. Dragging ras back in the ring

    Stephen A. G., Esposito D., Bagni R. K., McCormick F.

    Cancer Cell. 2014, 25(3) 272-281

  3. Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

    Hunter J. C., Manandhar A., Carrasco M. A., Gurbani D., Gondi S., Westover K. D.

    Mol.Cancer Res. 2015, 13 (9) 1325-1335

  4. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

    Vigil D., Cherfils J., Rossman K. L., Der C. J.

    Nat Rev. Drug. Discov. 2010, 10 (12) 842-857

  5. Induction of the Ras activator Son of Sevenless 1 by environmental pollutants mediates their effects on cellular proliferation

    Pierre S. Bats A. S., Chevallier A., Bui L. C., Ambolet-Camoit A., Garlatti M., Aggerbeck M., Barouki R., Coumoul X.

    Biochem. Pharmacol. 2011, 81(2) 304-313

  6. Mammalian son of sevenless Guanine nucleotide exchange factors: old concepts and new perspectives

    Rojas J. M., Oliva J. L., Santos E.

    Genes Cancer 2011, 2(3) 298-305

  7. Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis

    Jeng H. H., Taylor L. J., Bar-Sagi D.

    Nat. Commun. 2012, 3 1168