2. Academic Validation
  3. Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor

Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor

  • ACS Med Chem Lett. 2021 Apr 21;12(5):791-797. doi: 10.1021/acsmedchemlett.1c00063.
Malcolm P Huestis 1,  Matthew R Durk 2,  Charles Eigenbrot 3,  Paul Gibbons 1,  Thomas L Hunsaker 4,  Hank La 2,  Dennis H Leung 5,  Wendy Liu 1,  Shiva Malek 6,  Mark Merchant 4,  John G Moffat 7,  Christine S Muli 5,  Christine J Orr 4,  Brendan T Parr 1,  Frances Shanahan 6,  Christopher J Sneeringer 7,  Weiru Wang 3,  Ivana Yen 6,  Jianping Yin 3,  Joachim Rudolph 1,  Michael Siu 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 3 Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 4 Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 5 Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 6 Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 7 Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 34055227 DOI: 10.1021/acsmedchemlett.1c00063
Abstract

Structure-based optimization of a set of aryl urea Raf inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK Inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective Raf inhibitors reported to date.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-142160
    98.28%, RAF抑制剂
    Raf
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z