KRAS switch I/II pocket inhibitor | BI-2852

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Target protein: 
KRAS
Probe Name: 
BI-2852
MOLECULAR WEIGHT [DA]: 
516.6
In stock: 
997

Chemical structure

Highlights

BI-2852 is a potent inhibitor for in vitro use that directly targets GTP-bound KRAS, which is the major form present in cancer cells carrying KRAS mutations. BI-2852 binds to KRASG12D with a KD of 740 nM (ITC), inhibits GTP-KRASG12D binding to effectors like SOS1, CRAF and PI3Kα with an IC50 of 490, 770 and 500 nM. BI-2852 showed pERK(2h) modulation and antiproliferative effects in KRASmut cells (NCI-H358) at 5.8 µM and 6.7 µM.5

Together with the structurally similar negative control BI-2853 which is also available via opnMe.com, the probe BI-2852 can serve as an excellent small molecule tool inhibitor of KRAS for testing biological hypotheses in vitro.
Due to high demand, we have reduced for short time period the dose shipped from 5mg to 2.5mg per delivery.

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Target information

The three human RAS genes, KRAS, NRAS and HRAS encode four different RAS proteins (KRAS-4A, KRAS-4B, NRAS and HRAS) which belong to the protein family of small GTPases. The RAS proteins function as molecular switches between active GTP-bound and inactive GDP-bound conformations. RAS is the most frequently mutated oncogene in human cancers (~27%) with activating mutations mainly in codons 12, 13 and 61. The main mutation in codon 12 causes RAS activation by interfering with GAP binding and GAP-stimulated GTP hydrolysis. KRAS mutations rates are high in pancreatic (~90%), colorectal (~45%) and lung adenocarcinomas (~35%).1,2 KRAS could serve as an excellent drug target for many cancers, but direct inhibition of oncogenic RAS has proven to be challenging. After more than three decades of intense effort, the first anti-RAS therapies have just reached clinical application in the beginning of 2019.1-5

Complex of KRAS with BI-2852

Complex of KRAS with BI-2852

In vitro Activity

BI-2852 displays an IC50 of 490 nM in a GTP-KRASG12D::SOS1 AlphaScreen (AS) assay leading to low micromolar inhibition of pERK (in H358 cell line)5.

Probe name / Negative control

BI-2852

BI-2853

MW [Da]

516.6

516.6

ITC (KD) GCP-KRASG12D [µM]a

0.74

n.d.

ITC (KD) GCP-KRASwt [µM]a

7.5

n.d.

ITC (KD) GDP-KRASG12D [µM]a

2.0

n.d.

ITC (KD) GDP-KRASwt [µM]a

1.1

n.d.

AS (IC50) GTP-KRASG12D::SOS1 [nM]a

490

4400

AS (IC50) GTP-KRASG12D::CRAF [nM]a

770

n.d.

AS (IC50) GTP-KRASG12D::PI3Kα [nM]a

500

n.d.

AS (IC50) GDP-KRASG12D::SOS1 [nM]a

260

2500

AS (IC50) GTP-KRASwt::SOS1 [nM]a

490

n.d.

EC50 pERK H358 cells (2 h) [µM]a

5.8

> 50

EC50 H358 cells (low serum) [µM]a

6.7

n.d.

a for assay conditions please refer to reference 5

In vitro DMPK and CMC parameters

Probe name / Negative control

BI-2852

BI-2853

logP

2.6

2.6

Solubility @ pH 6.8 [µg/ml]

18

21

CACO permeability @ pH 7.4 [*10-6 cm/s]

5.0

<1.15

CACO efflux ratio

2.1

n.d.

MDCK permeability Pappa-b/b-a @ 1µM [10-6 cm/s]

n.d.

n.d.

MDCK efflux ratio

n.d.

n.d.

Microsomal stability (human/mouse/rat) [% QH]

91 / 93 / 90

92 / 95 / 86

Hepatocyte stability (human/mouse/rat) [% QH]

12 / 21 / 25

12 / 69 / 52

Plasma protein binding (human/mouse/rat) [%]

98.8 / 99.5 / 98.5

98.7 / 99.1 / 98.6

CYP 3A4 (IC50) [µM]

4.4

n.d.

CYP 2C8 (IC50) [µM]

8.4

n.d.

CYP 2C9 (IC50) [µM]

4.8

n.d.

CYP 2C19 (IC50) [µM]

11.0

n.d.

CYP 2D6 (IC50) [µM]

15.0

n.d.

In vivo DMPK parameters

No data available, BI-2852 is an in vitro tool compound.

In vivo pharmacology

No data available, BI-2852 is an in vitro tool compound

Negative control

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
516.6

BI-2853 is the less active enantiomer of BI-2853. It shows no effect on cells and is around 10-fold less potent in the AS assays.

BI-2853  which serves as a negative control

BI-2853 which serves as a negative control

Selectivity

Selectivity data are not available at this point in time.

Bi-3663

SELECTIVITY DATA AVAILABLE

Cerep®

No

Panlabs®

No

Invitrogen®

No

DiscoverX®

No

Dundee

No

Co-crystal structure of the BI probe compound and the target protein

The Xray crystal structure of target in complex with BI-2852 is available (PDB code: 6GJ7)5.

Summary

The in vitro tool compound BI-2852 is a potent nanomolar inhibitor of the KRAS switch I/II pocket and directly inhibits both the active and inactive forms of KRAS.

Supplementary data

References

  1. Targeting Mutant KRAS for Anticancer Therapeutics: A Review of Novel Small Molecule Modulators

    Wang Y., Kaiser C. E., Frett B., and Li H.

    J. Med. Chem. 2013, 56, 5219−5230.

  2. Drugging the undruggable RAS: Mission possible?

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

    Nat. Rev. Drug. Discov. 2014, 13, 828-851.

  3. Dragging ras back in the ring

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

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

  4. RAS isoforms and mutations in cancer at a glance

    Hobbs G. A., Der C. J., Rossman K. L.

    J. Cell Science 2016, 129, 1287-1292.

  5. Drugging an “undruggable” pocket on KRAS

    Kessler D., Gmachl M., Mantoulidis A., Martin L. J., Zoephel A., Mayer M., Gollner A., Covini D., Fischer S., Gerstberger T., Gmaschitz T., Goodwin C., Greb P., Häring D., Hela W., Hoffmann J., Karolyi-Oezguer J., Knesl P., Kornigg S., Koegl M., Kousek R., Lamarre L., Moser F., Munico-Martinez S., Peinsipp C., Phan J., Rinnenthal J., Sai J., Salamon C., Scherbantin Y., Schipany K., Schnitzer R., Schrenk A., Sharps B., Siszler G., Sun Q., Waterson A., Wolkerstorfer B., Zeeb M., Pearson M., Fesik S. W. and McConnell D. B.

    PNAS 2019, 116 (32), 15823-15829.

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