- Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction
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Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal ‘‘lid’’ segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds.
- Neochoritis, Constantinos G.,Atmaj, Jack,Twarda-Clapa, Aleksandra,Surmiak, Ewa,Skalniak, Lukasz,K?hler, Lisa-Maria,Muszak, Damian,Kurpiewska, Katarzyna,Kalinowska-T?u?cik, Justyna,Beck, Barbara,Holak,D?mling, Alexander
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supporting information
(2019/08/20)
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- PAIN TREATING COMPOUNDS AND USES THEREOF
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The present invention relates to compounds useful in the modulation of ion channel activity in cells. The invention also relates to use of these compounds in the treatment of pain, and pharmaceutical compositions containing these compounds and methods for their preparation.
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- Benzyloxybenzylammonium chlorides: Simple amine salts that display anticonvulsant activity
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Several antiepileptic drugs exert their activities by inhibiting Na + currents. Recent studies demonstrated that compounds containing a biaryl-linked motif (Ar-X-Ar′) modulate Na+ currents. We, and others, have reported that compound
- Lee, Hyosung,Gold, Alexander S.,Yang, Xiao-Fang,Khanna, Rajesh,Kohn, Harold
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p. 7655 - 7662
(2014/01/06)
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- Merging the structural motifs of functionalized amino acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities
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Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3′′-fluoro) benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.
- Salomé, Christophe,Salomé-Grosjean, Elise,Stables, James P.,Kohn, Harold
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supporting information; experimental part
p. 3756 - 3771
(2010/07/16)
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