Important Compound Classes
Title
(1H-Indol-5-yl)acrylamide Derivatives as Inhibitors of TEAD Proteins and the HIPPO-YAP1/TAZ Signaling Cascade for the Treatment of Cancer
Patent Publication Number
WO 2021/204823 A1
Publication Date
October 14, 2021
Priority Application
EP 20315128.7 and EP 20315438.0
Priority Date
April 7, 2020 and October 22, 2020
Inventors
Fett, E.; Venier, O.
Assignee Company
SANOFI, France
Disease Area
Cancer
Biological Target
TEAD
Summary
Transcriptional enhanced associate domain (TEAD) proteins are transcription factors comprised of four family members (TEAD 1–4) that function in modulating gene expression in response to the HIPPO pathway. TEAD proteins preferentially associate with transcription coactivators yes associated protein 1 (YAP1) or transcriptional coactivator with PDZ-binding motif (TAZ, also known as WWTR1). YAP1-TEAD or TAZ-TEAD bind to DNA and initiate the transcription of multiple different genes involved in cell proliferation, survival, mobility, stemness, and differentiation.
The deregulation of HIPPO-YAP1/TAZ-TEAD activity is at the origin of tumor progression and resistance to therapy in several different cancer indications. In humans, genetic alterations in the pathway are most prevalent for NF2 (neurofibromin), an upstream regulator of the core HIPPO pathway, that has been linked to the heritable cancer syndrome and that has been classified as a tumor suppressor gene. The number of tumor types that depend on YAP1-TEAD activation are from breast, ovarian, uterine, prostate, lung, gastric, colorectal, bladder, pancreatic, and liver cancers. Thus, the HIPPO-YAP/TAZ/TEAD pathway is a key player in cancer development and tumor maintenance and targeting this pathway is key for cancer treatment.
The present application describes a series of novel indole compounds as TEAD inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
R1 = single bond and (C1–C4) alkylene group;
R2 = (C1–C4) alkyl group or substituted with one or more F atoms, (C1–C3) alkoxy group or substituted with one or more F atoms, phenyl group unsubstituted or substituted with one or more R3 groups, (C4–C8) cycloalkyl group unsubstituted or substituted with one or more R5 groups, (C4–C8) heterocyclyl group unsubstituted or substituted with one or more R6 groups, and NR9R10 group;
R4 = H atom and (C1–C4) alkyl group;
R7 = H atom, nitrile group, and (C1–C4) alkyl group unsubstituted or substituted with (C1–C3) alkoxy group or hydroxy group, COO(C1–C4) alkyl and CONH2 group;
R8 = H atom and (C1–C4) alkyl group unsubstituted or substituted with di(C1–C4) alkylamino group;
R11 = H atom, F atom and Cl atom; and
n = 0 or 1.
Key Structures
Biological Assay
The TEAD-luciferase reporter assay was performed. The compounds described in this application were tested for their ability to inhibit TEAD. The TEAD IC50 (nM) are shown in the following Table.
Biological Data
The Table below shows representative
compounds were tested for TEAD inhibition. The biological data obtained
from testing representative examples are listed in the following Table.
Claims
Total claims: 15
Compound claims: 13
Pharmaceutical composition claims: 1
Medicament claims: 1
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The author declares no competing financial interest.