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Comment
. 2020 Feb 18;117(7):3363-3364.
doi: 10.1073/pnas.1918164117. Epub 2020 Feb 11.

The small molecule BI-2852 induces a nonfunctional dimer of KRAS

Timothy H Tran  1 , Patrick Alexander  1 , Srisathiyanarayanan Dharmaiah  1 , Constance Agamasu  1 , Dwight V Nissley  1 , Frank McCormick  1   2 , Dominic Esposito  1 , Dhirendra K Simanshu  1 , Andrew G Stephen  1 , Trent E Balius  3
Affiliations
Comment

The small molecule BI-2852 induces a nonfunctional dimer of KRAS

Timothy H Tran et al. Proc Natl Acad Sci U S A. .
No abstract available

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Conflict of interest statement

Competing interest statement: F.M. is a consultant for the following companies: AduroBiotech; Amgen; Daiichi, Ltd.; PellePharm; Pfizer, Inc.; PMV Pharma; and Portola Pharmaceuticals. F.M. is Scientific Director of the National Cancer Institute RAS Initiative at Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc. F.M. is a consultant for and cofounder of the following companies: Avidity, BridgeBio, KGen, and Quartz.

Figures

Fig. 1.
Fig. 1.
Dimer of KRAS with BI-2852. (A) Cartoon of BI-2852 KRAS dimer. Lig1 (cyan) and Lig2 (magenta) interact with both Ras1 (beige) and Ras2 (orange). (B) KRAS (ribbons) and key side chains are shown. (C) Zoom-in of the binding site: salt–bridge interactions shown (dashed lines). (D) Lid (green) and Basin (purple) are indicated on Ras1. Both Lig1 and Lig2 are shown on Ras1. The indole rings, colored green and purple, engage the Lid and Basin, respectively. (E) Absorbance A280 plotted as a function of elution volume: KRAS G12D-GppNHp with BI-2852 (orange) and apo KRAS G12D-GppNHp (blue).
See this image and copyright information in PMC

Comment in

  • Reply to Tran et al.: Dimeric KRAS protein-protein interaction stabilizers.
    Kessler D, Gollner A, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A, Mayer M, 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 SW, McConnell DB. Kessler D, et al. Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3365-3367. doi: 10.1073/pnas.1921236117. Epub 2020 Feb 11. Proc Natl Acad Sci U S A. 2020. PMID: 32047042 Free PMC article. No abstract available.

Comment on

  • Drugging an undruggable pocket on KRAS.
    Kessler D, Gmachl M, Mantoulidis A, Martin LJ, 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 SW, McConnell DB. Kessler D, et al. Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15823-15829. doi: 10.1073/pnas.1904529116. Epub 2019 Jul 22. Proc Natl Acad Sci U S A. 2019. PMID: 31332011 Free PMC article.

References

    1. Kessler D., et al. , Drugging an undruggable pocket on KRAS. Proc. Natl. Acad. Sci. U.S.A. 116, 15823–15829 (2019). - PMC - PubMed
    1. Tran T. H., et al. , Data from “SI. The small molecule BI-2852 induces a non-functional dimer of KRAS.” Figshare. 10.6084/m9.figshare.11425995. Deposited 30 December 2019. - DOI - PubMed

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