Nicotinamide
N
-methyltransferase (NNMT) catalyzes
the methylation of nicotinamide to form
N
-methylnicotinamide.
Overexpression of NNMT is associated with a variety of diseases, including
a number of cancers and metabolic disorders, suggesting a role for
NNMT as a potential therapeutic target. By structural modification
of a lead NNMT inhibitor previously developed in our group, we prepared
a diverse library of inhibitors to probe the different regions of
the enzyme’s active site. This investigation revealed that
incorporation of a naphthalene moiety, intended to bind the hydrophobic
nicotinamide binding pocket via π–π stacking interactions,
significantly increases the activity of bisubstrate-like NNMT inhibitors
(half-maximal inhibitory concentration
1.41 μM). These findings are further supported by isothermal
titration calorimetry binding assays as well as modeling studies.
The most active NNMT inhibitor identified in the present study demonstrated
a dose-dependent inhibitory effect on the cell proliferation of the
HSC-2 human oral cancer cell line.
Nicotinamide
N
-methyltransferase (NNMT) methylates
nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA).
NNMT overexpression has been linked to a variety of diseases, most
prominently human cancers, indicating its potential as a therapeutic
target. The development of small-molecule NNMT inhibitors has gained
interest in recent years, with the most potent inhibitors sharing
structural features based on elements of the nicotinamide substrate
and the
S
-adenosyl-
l
-methionine (SAM) cofactor.
We here report the development of new bisubstrate inhibitors that
include electron-deficient aromatic groups to mimic the nicotinamide
moiety. In addition, a
trans
-alkene linker was found
to be optimal for connecting the substrate and cofactor mimics in
these inhibitors. The most potent NNMT inhibitor identified exhibits
an IC
50
value of 3.7 nM, placing it among the most active
NNMT inhibitors reported to date. Complementary analytical techniques,
modeling studies, and cell-based assays provide insights into the
binding mode, affinity, and selectivity of these inhibitors.
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-L-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly...
A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.
As erieso fh ighly tunable bifunctional phosphine-squaramide H-bond donor organocatalysts 6 has been synthesizedf rom inexpensivea nd commercially available b-amino alcohols in moderate yields.C atalyst 6f can efficiently promote the asymmetric Morita-Baylis-Hillman (MBH) reaction of N-alkyl isatins with acrylate estersp roviding the chiral 3-substituted 3-hydroxy-2-oxindoles in good yields and enantioselectivities( up to 93 % yield and9 5% ee), in which the challenging substrate tert-butyl acrylate 9d,p rovided the best ee value to date.M oreover, this methodology was applied successfully in the synthesis of chiral cyclic spiropyrrolizidineoxindolea nd g-butyrolactone derivatives without enantioselectivity deterioration. Thep ossible mechanism of this MBH reactionw as also investigated by 31 PNMR, ESI-MS and KIE studies.T he KIE experiments show that the electrophilic addition of N-methyl isatin to the complexo f acrylate ester and phophine-squaramide is the ratedeterming step of the asymmetric MBH reaction.
Selective CDK2 inhibitors have the potential to provide
effective
therapeutics for CDK2-dependent cancers and for combating drug resistance
due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification
induced by treatment of CDK4/6 inhibitors. Generative models that
take advantage of deep learning are being increasingly integrated
into early drug discovery for hit identification and lead optimization.
Here we report the discovery of a highly potent and selective macrocyclic
CDK2 inhibitor QR-6401 (23) accelerated by the application
of generative models and structure-based drug design (SBDD). QR-6401
(23) demonstrated robust antitumor efficacy in an OVCAR3
ovarian cancer xenograft model via oral administration.
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