OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.
Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non -small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II -driven human tumor model. [Mol Cancer Ther 2007;6(8):2158 -67]
The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that has a critical role in mitogenic signalling during embryogenesis and an antiapoptotic role in the survival and progression of many human tumours. Here, we present the crystal structure of the tyrosine kinase domain of IGF1R (IGF1RK), in its unphosphorylated state, in complex with a novel com-, which we show is a potent inhibitor of both the unphosphorylated (basal) and phosphorylated (activated) states of the kinase. PQIP interacts with residues in the ATP-binding pocket and in the activation loop, which confers specificity for IGF1RK and the highly related insulin receptor (IR) kinase. In this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the activation loop of an symmetry (two-fold)-related molecule. This dimeric arrangement affords, for the first time, a visualization of the initial trans-phosphorylation event in the activation loop of an RTK, and provides a molecular rationale for a naturally occurring mutation in the activation loop of the IR that causes type II diabetes mellitus.
Racemic cis-4-aminocyclopent-2-en-1-ols were synthesized in three steps utilizing hetero Diels-Alder chemistry. Starting from suitably protected hydroxylamines, oxidization with sodium periodate and trapping with cyclopentadiene afforded cycloadducts (()-5a-d. The N-O bond of the cycloadducts was reduced with Mo(CO) 6 to afford (()-cis-4-aminocyclopent-2-en-1-ols (()-6ad. These compounds, or their corresponding acetates, were kinetically resolved by enzymatic acetylation or hydrolysis, respectively. Enzymatic acetylation of cis-N-(benzylcarbamoyl)-4aminocyclopent-2-enol [(()-6a] with Candida antarctica B lipase and Pseudomonas species lipase gave the corresponding acetate (-)-7a in 90% and 92% ee, respectively, after 40% conversion. Enzymatic hydrolysis of cis-N-acetyl-4-aminocyclopent-2-enol 1-O-acetate (()-7d with electric eel acetylcholine esterase was successful in providing both cis-N-acetyl-4-aminocyclopent-2-enols (+)-6d and (+)-7d in 92% ee (99% ee after a single recrystallization) after 40% conversion. Further synthetic transformations of these resolved synthetic building blocks and derivatives are also reported.
The
activity of the secreted phosphodiesterase autotaxin produces
the inflammatory signaling molecule LPA and has been associated with
a number of human diseases including idiopathic pulmonary fibrosis
(IPF). We screened a single DNA-encoded chemical library (DECL) of
225 million compounds and identified a series of potent inhibitors.
Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small
molecule. Cocrystallization of compound 1 with human
autotaxin demonstrated that it has a novel binding mode occupying
both the hydrophobic pocket and a channel near the autotaxin active
site. Compound 1 inhibited the production of LPA in human
and mouse plasma at nanomolar levels and showed efficacy in a mouse
model of human lung fibrosis. After successfully completing IND-enabling
studies, compound 1 was approved by the FDA for a Phase
I clinical trial. These results demonstrate that DECL hits can be
readily optimized into clinical candidates.
SUMMARY
Metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in the misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo.
Because of compensatory crosstalk between IGF-1R and IR, dual IGF-1R and IR tyrosine kinase inhibitors may have superior anti-tumor activity compared to anti-IGF-1R specific antibodies. The clinical success for IGF-1R/IR inhibitors may ultimately be dependent upon our ability to correctly administer these agents to the right niche patient subpopulation using single agent therapy, when appropriate, or using the right combination therapy.
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