RESUMO
Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays. CA-4948 demonstrated moderate to high selectivity in a panel of 329 kinases as well as exhibited desirable ADME and PK profiles including good oral bioavailability in mice, rat, and dog and showed >90% tumor growth inhibition in relevant tumor models with excellent correlation with in vivo PD modulation. CA-4948 was well tolerated in toxicity studies in both mouse and dog at efficacious exposure. The overall profile of CA-4948 prompted us to select it as a clinical candidate for evaluation in patients with relapsed or refractory hematologic malignancies including non-Hodgkin lymphoma and acute myeloid leukemia.
RESUMO
An acyclic tripeptide based on a heterochiral D-pro-L-pro template shows a propensity to exist as a 3(10) helical conformation and can be cyclized, via ring-closing metathesis, to the corresponding cyclic tetrapeptides without disrupting the helical conformations in CDCl(3) as well as in DMSO-d(6) solutions. The detailed conformational studies were carried out by using NMR spectroscopy, X-ray crystallography, molecular dynamic simulations, and circular dichroism spectroscopy.
Assuntos
Dipeptídeos/química , Oligopeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Amidas/química , Dicroísmo Circular , Cristalografia por Raios X , Ciclização , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ressonância Magnética Nuclear Biomolecular , EstereoisomerismoRESUMO
A cis-proline derived cyclic mimic of a type VI beta-turn is synthesized via a ring-closing metathesis reaction. The solution NMR conformational study indicates that the major conformer of the cyclic peptide adopts a type VIa beta-turn in CDCl(3) and a type VIb beta-turn in DMSO-d(6).
Assuntos
Modelos Moleculares , Peptídeos Cíclicos/síntese química , Prolina/química , Estrutura Secundária de Proteína , Ciclização , Espectroscopia de Ressonância Magnética , Conformação Molecular , Mimetismo Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
A reverse turn induced (gamma/beta-turn) cyclization of tripeptides 1 can be performed in a ring closing metathesis reaction with Grubbs' catalyst to the corresponding cyclic peptides 2. These cyclic peptides may be useful probes as a conformationally constrained mimic of the bioactive conformation of structurally related HIV protease inhibitors.
