- Peptide-Drug conjugate gnrh-sunitinib targets angiogenesis selectively at the site of action to inhibit tumor growth
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The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues
- Argyros, Orestis,Karampelas, Theodoros,Asvos, Xenophon,Varela, Aimilia,Sayyad, Nisar,Papakyriakou, Athanasios,Davos, Constantinos H.,Tzakos, Andreas G.,Fokas, Demosthenes,Tamvakopoulos, Constantin
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- CONJUGATES OF AMPK INHIBITORS AND PROTAC DEGRADERS AND RELATED USES
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The present disclosure relates to compounds of Formula (I): T-L-D, stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein T is an AMPK inhibiting moiety; L is a linking moiety; and D is a PROTAC degrading moiety. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK), degrading AMPK protein, and/or treat cancer in a subject.
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Paragraph 0333; 0339-0340; 0346
(2022/01/12)
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- AMP-ACTIVATED PROTEIN KINASE INHIBITORS AND METHODS OF MAKING AND USING THE SAME
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The present disclosure relates to compounds of Formula (I): (I); stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK) and treat cancer in a subject.
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Page/Page column 64-65; 69-70
(2021/01/23)
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- Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors
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AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.
- Backos, Donald S.,Casalvieri, Kimberly A.,Jordan, Craig T.,Matheson, Christopher J.,Minhajuddin, Mohammed,Reigan, Philip
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- N-desethylsunitinib phosphoramide derivatives and preparation method thereof
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The invention relates to N-desethylsunitinib phosphoramide derivatives represented by a general formula (I) shown in the description, stereoisomers of the derivatives or pharmaceutically-acceptable salts of the derivatives, a preparation method of the der
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Paragraph 0055; 0063-0068
(2019/08/20)
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- Synthesis of 2H- and 13C-labelled sunitinib and its primary metabolite
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Sunitinib (Sutent, Pfizer) was approved in 2006 for the treatment of gastrointestinal and renal cancer. Isotope-labelled derivatives have already been prepared for PET and ADME radiography. The preparation of 13C- and 2H-labelled internal standards of sunitinib (SU11248) and its primary metabolite (SU12662) for LC-MS analysis of human blood samples is presented. Copyright
- Elsinghorst, Paul W.,Guetschow, Michael
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p. 360 - 365
(2011/06/25)
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