Method of inhibiting DYRK1B
Inventors
ABERGER, Fritz • Gruber, Wolfgang • Leban, Johann • KOHLHOF, Hella • Vitt, Daniel • Baumgartner, Roland
Assignees
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Publication Number
US-9951050-B2
Publication Date
2018-04-24
Expiration Date
Abstract
The present invention relates to a DYRK1B inhibitor for use in the treatment of cancer, wherein in said cancer and/or in cells of said cancer the hedgehog signaling pathway is activated, and in particular the activation of the hedgehog signaling pathway is independent of signaling by the G protein-coupled receptor Smoothened.
Core Innovation
The invention concerns DYRK1B inhibition, also referred to as MIRK, as an anti-cancer strategy in cancers in which the hedgehog signaling pathway is activated. The disclosed approach includes administering to a subject an effective amount of a DYRK1B inhibitor, including small molecules and compounds of formula (I), in relation to Hedgehog/GLI signaling output, including GLI1 and GLI2 activity.
A central problem addressed is that Hedgehog/GLI signaling can be activated independently of Smoothened signaling, including contexts in which cancers are described as not responsive to Smoothened inhibitor therapy. The disclosed treatment concept therefore targets DYRK1B in cancers where hedgehog signaling pathway activation occurs independently of Smoothened, with the aim of suppressing hedgehog pathway activity downstream at GLI1 and GLI2.
The document provides mechanistic and functional rationale linking DYRK1B activity to hedgehog/GLI signaling. It describes DYRK1B inhibition and comparisons to DYRK1A knockdown or pharmacologic inhibition, with reported effects including downregulation of GLI1 and GLI2, and reference to HHIP and PTCH1 as hedgehog-pathway associated readouts in the described background.
Claims Coverage
The document contains three independent claims. Across them, the inventive coverage centers on treating cancer with activated hedgehog signaling by administering a DYRK1B inhibitor, including defined constraints on Smoothened independence and Smoothened-inhibitor non-responsiveness, and includes an in vitro DYRK1B inhibition method using a DYRK1B inhibitor in a sample containing cancer cells with activated hedgehog signaling.
Treating cancer with activated hedgehog signaling using a dyRK1B inhibitor
Administering to a subject in need thereof an effective amount of a DYRK1B inhibitor for treating cancer in which the hedgehog signaling pathway is activated.
Treating cancer with activated hedgehog signaling using a formula (I) DYRK1B inhibitor
Administering to a subject in need thereof an effective amount of a DYRK1B inhibitor that is a compound of formula (I) for treating cancer in which the hedgehog signaling pathway is activated.
In vitro inhibition of DYRK1B in a sample containing cancer cells with activated hedgehog signaling
In vitro inhibiting DYRK1B by adding a DYRK1B inhibitor to a sample comprising cancer cells, wherein the hedgehog signaling pathway is activated.
Overall, the claim coverage focuses on DYRK1B inhibition as a treatment for activated hedgehog signaling in cancer, with further disclosed selection and constraint concepts in dependent claims relating to independence from Smoothened signaling and lack of responsiveness to Smoothened inhibitor therapy, and with one independent claim restricting the DYRK1B inhibitor to compounds of formula (I).
Stated Advantages
Maintained efficacy in Smoothened inhibitor-resistant models where hedgehog activation is described as independent of Smoothened signaling.
Downregulation of GLI1 and GLI2 activity in connection with DYRK1B inhibition in the described mechanistic and functional rationale.
Documented Applications
Treating cancer in subjects where the hedgehog signaling pathway is activated using a DYRK1B inhibitor.
Treating cancers characterized as not responsive to Smoothened inhibitor therapy, including cases where hedgehog activation is independent of Smoothened signaling.
In vitro inhibition of DYRK1B by adding a DYRK1B inhibitor to a sample comprising cancer cells with activated hedgehog signaling.
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