2. Academic Validation
  3. Drugging an undruggable pocket on KRAS

Drugging an undruggable pocket on KRAS

  • Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15823-15829. doi: 10.1073/pnas.1904529116.
Dirk Kessler 1,  Michael Gmachl 1,  Andreas Mantoulidis 1,  Laetitia J Martin 1,  Andreas Zoephel 1,  Moriz Mayer 1,  Andreas Gollner 1,  David Covini 1,  Silke Fischer 1,  Thomas Gerstberger 1,  Teresa Gmaschitz 1,  Craig Goodwin 2,  Peter Greb 1,  Daniela Häring 1,  Wolfgang Hela 1,  Johann Hoffmann 1,  Jale Karolyi-Oezguer 1,  Petr Knesl 1,  Stefan Kornigg 1,  Manfred Koegl 1,  Roland Kousek 1,  Lyne Lamarre 1,  Franziska Moser 3,  Silvia Munico-Martinez 1,  Christoph Peinsipp 1,  Jason Phan 2,  Jörg Rinnenthal 1,  Jiqing Sai 2,  Christian Salamon 1,  Yvonne Scherbantin 1,  Katharina Schipany 1,  Renate Schnitzer 1,  Andreas Schrenk 1,  Bernadette Sharps 1,  Gabriella Siszler 1,  Qi Sun 2,  Alex Waterson 4 5,  Bernhard Wolkerstorfer 1,  Markus Zeeb 3,  Mark Pearson 1,  Stephen W Fesik 2 4 5,  Darryl B McConnell 6
Affiliations

Affiliations

  • 1 Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120 Vienna, Austria.
  • 2 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37235.
  • 3 Discovery Research, Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach an der Riss, Germany.
  • 4 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37235.
  • 5 Department of Chemistry, Vanderbilt University, Nashville, TN 37235.
  • 6 Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120 Vienna, Austria; darryl.mcconnell@boehringer-ingelheim.com.
PMID: 31332011 DOI: 10.1073/pnas.1904529116
Abstract

The 3 human Ras genes, KRAS, NRAS, and HRAS, encode 4 different Ras proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in Ras are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting Ras has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be "undruggable," between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.

Keywords

KRAS; NMR; fragment-based drug design; oncology; structure-based drug design.

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