3 research outputs found
Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors
Blockade of aberrant Wnt signaling
is an attractive therapeutic
approach in multiple cancers. We developed and performed a cellular
high-throughput screen for inhibitors of Wnt secretion and pathway
activation. A lead structure (GNF-1331) was identified from the screen.
Further studies identified the molecular target of GNF-1331 as Porcupine,
a membrane bound O-acyl transferase. Structure–activity relationship
studies led to the discovery of a novel series of potent and selective
Porcupine inhibitors. Compound <b>19</b>, GNF-6231, demonstrated
excellent pathway inhibition and induced robust antitumor efficacy
in a mouse MMTV-WNT1 xenograft tumor model
(<i>R</i>)‑2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors
Deregulated
kinase activities of tropomyosin receptor kinase (TRK)
family members have been shown to be associated with tumorigenesis
and poor prognosis in a variety of cancer types. In particular, several
chromosomal rearrangements involving TRKA have been reported in colorectal,
papillary thyroid, glioblastoma, melanoma, and lung tissue that are
believed to be the key oncogenic driver in these tumors. By screening
the Novartis compound collection, a novel imidazopyridazine TRK inhibitor
was identified that served as a launching point for drug optimization.
Structure guided drug design led to the identification of (<i>R</i>)-2-phenylpyrrolidine substituted imidazopyridazines as
a series of potent, selective, orally bioavailable pan-TRK inhibitors
achieving tumor regression in rats bearing KM12 xenografts. From this
work the (<i>R</i>)-2-phenylpyrrolidine has emerged as an
ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of
its shape complementarity to the hydrophobic pocket of TRKs
Synthesis, Structure–Activity Relationships, and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor 5‑Chloro‑<i>N</i>2‑(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)‑<i>N</i>4‑(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) Currently in Phase 1 and Phase 2 Clinical Trials
The synthesis, preclinical profile,
and in vivo efficacy in rat xenograft models of the novel and selective
anaplastic lymphoma kinase inhibitor <b>15b</b> (LDK378) are
described. In this initial report, preliminary structure–activity
relationships (SARs) are described as well as the rational design
strategy employed to overcome the development deficiencies of the
first generation ALK inhibitor <b>4</b> (TAE684). Compound <b>15b</b> is currently in phase 1 and phase 2 clinical trials with
substantial antitumor activity being observed in ALK-positive cancer
patients