873077-70-4Relevant articles and documents
CONJUGATES OF AMPK INHIBITORS AND PROTAC DEGRADERS AND RELATED USES
-
Paragraph 0333; 0344, (2022/01/12)
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.
DENDRIMER COMPOSITIONS AND METHODS FOR DRUG DELIVERY TO THE EYE
-
, (2021/06/11)
Dendrimer compositions and methods for the treatment of one or more inflammatory and/or angiogenic diseases and/or disorders of the eye include hydroxyl-terminated dendrimers complexed or conjugated with one or more active agents for the treatment or alleviation of one or more symptoms of the diseases of the eye, and/or for diagnosing the diseases and/or disorders of the eye. The dendrimers may include one or more ethylene diamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation-4, 5, 6, 7, 8, 9, or 10 dendrimers. The active agents may be VEGFR tyrosine kinase inhibitors including sunitinib or analogues thereof. Preferably, the compositions are suitable for administration via a systemic route to target activated microglia/macrophages in retina/choroid.
AMP-ACTIVATED PROTEIN KINASE INHIBITORS AND METHODS OF MAKING AND USING THE SAME
-
Page/Page column 68, (2021/01/23)
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.
Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors
Backos, Donald S.,Casalvieri, Kimberly A.,Jordan, Craig T.,Matheson, Christopher J.,Minhajuddin, Mohammed,Reigan, Philip
, (2020/04/22)
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.
