Structural effects of morpholine replacement in ZSTK474 on Class I PI3K isoform inhibition: Development of novel MEK/PI3K bifunctional inhibitors.

Autor: Van Dort ME; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: mvandort@umich.edu., Jang Y; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: jyoungso@umich.edu., Bonham CA; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: bonhachr@umich.edu., Heist K; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: heistka@umich.edu., Palagama DSW; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: dilruksp@umich.edu., McDonald L; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: mcdonalu@umich.edu., Zhang EZ; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: edzhang@umich.edu., Chenevert TL; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: tlchenev@umich.edu., Luker GD; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA. Electronic address: gluker@umich.edu., Ross BD; Center for Molecular Imaging, The University of Michigan Medical School, MI, 48109, USA; Department of Radiology, The University of Michigan Medical School, MI, 48109, USA; Department of Biological Chemistry, The University of Michigan Medical School, MI, 48109, USA. Electronic address: bdross@umich.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Feb 05; Vol. 229, pp. 113996. Date of Electronic Publication: 2021 Nov 14.
DOI: 10.1016/j.ejmech.2021.113996
Abstrakt: Established roles for PI3K and MAPK signaling pathways in tumorigenesis has prompted extensive research towards the discovery of small-molecule inhibitors as cancer therapeutics. However, significant compensatory regulation exists between these two signaling cascades, leading to redundancy among survival pathways. Consequently, initial clinical trials aimed at either PI3K or MEK inhibition alone have proven ineffective and highlight the need for development of targeted and innovative therapeutic combination strategies. We designed a series of PI3K inhibitor derivatives wherein a single morpholine group of the PI3K inhibitor ZSTK474 was substituted with a variety of 2-aminoethyl functional groups. Analogs with pendant hydroxyl or methoxy groups maintained low nanomolar inhibition towards PI3Kα, PI3Kγ, and PI3Kδ isoforms in contrast to those with pendant amino groups which were significantly less inhibitory. Synthesis of prototype PI3K/MEK bifunctional inhibitors (6r, 6s) was guided by the structure-activity data, where a MEK-targeting inhibitor was tethered directly via a short PEG linker to the triazine core of the PI3K inhibitor analogs. These compounds (6r, 6s) displayed nanomolar inhibition towards PI3Kα, δ, and MEK (IC 50 ∼105-350 nM), and low micromolar inhibition for PI3Kβ and PI3Kγ (IC 50 ∼1.5-3.9 μM) in enzymatic inhibition assays. Cell viability assays demonstrated superior anti-proliferative activity for 6s over 6r in three tumor-derived cell lines (A375, D54, SET-2), which correlated with inhibition of downstream AKT and ERK1/2 phosphorylation. Compounds 6r and 6s also demonstrated in vivo tolerability with therapeutic efficacy through reduction of kinase activation and amelioration of disease phenotypes in the JAK2V617F mutant myelofibrosis mouse cancer model. Taken together, these results support further structure optimization of 6r and 6s as promising leads for combination therapy in human cancer as a new class of PI3K/MEK bifunctional inhibitors.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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