A5044751426- Asthma and respiratory diseases
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Synthesis and biological activity
- Respiratory and Cough-Related Research
- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Cell Adhesion Molecules Research
- Peptidase Inhibition and Analysis
- Inhalation and Respiratory Drug Delivery
- Drug Transport and Resistance Mechanisms
- Acute Myeloid Leukemia Research
- IL-33, ST2, and ILC Pathways
- RNA Interference and Gene Delivery
- Pharmacogenetics and Drug Metabolism
- Gastrointestinal motility and disorders
- Neuropeptides and Animal Physiology
- Crystallization and Solubility Studies
- Biochemical and Structural Characterization
- X-ray Diffraction in Crystallography
- PI3K/AKT/mTOR signaling in cancer
- Immune Response and Inflammation
Rockefeller University
2024
Bridge Pharma (United States)
2021-2023
La Roche College
1994-2012
Roche (Switzerland)
2000-2005
Consorzio Milano Ricerche
1998
Roche (Italy)
1998
Temple University
1990-1992
Wilmington University
1992
The activity of the secreted phosphodiesterase autotaxin produces inflammatory signaling molecule LPA and has been associated with a number human diseases including idiopathic pulmonary fibrosis (IPF). We screened single DNA-encoded chemical library (DECL) 225 million compounds identified series potent inhibitors. Optimization this led to discovery compound 1 (X-165), highly potent, selective, bioavailable small molecule. Cocrystallization demonstrated that it novel binding mode occupying...
The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid (AML), but its therapeutic potential remains unclear. We describe potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from by blocking YEATS domain interaction with acylated histones. Cell lines primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen...
Evasion of apoptosis is critical for the development and growth tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) an antiapoptotic member Bcl-2 family, associated with tumor aggressiveness, poor survival, drug resistance. Development Mcl-1 inhibitors implies blocking protein-protein interactions, generally requiring a lengthy optimization process large, complex molecules. Herein, we describe use DNA-encoded chemical library synthesis screening to directly generate complex, yet...
Tumor necrosis factor (TNF) has been implicated in the pathophysiology of a number inflammatory diseases lung. Using TNF receptor fusion protein, Ro 45-2081, our study investigated involvement allergic responses airways sensitized guinea pigs and Brown-Norway rats. Sensitized exhibited an enhanced airway reactivity to substance P (1-10 micrograms/kg, i.v.) at 6 hr after antigen challenge which was inhibited (P < .05) by 45-2081 (3 mg/kg, i.p.). Treatment with (1-3 i.p.) dose-dependently...
Ro 25-1553, a cyclic peptide analog of vasoactive intestinal (VIP), was designed to overcome many the deficiencies inherent in this natural neuropeptide. On isolated guinea pig tracheal smooth muscle, 25-1553 produces concentration-dependent relaxation contractile responses number different spasmogens. Depending on stimulus, is 24 89 times more potent than VIP as relaxant trachea. The high potency extends studies isolated, histamine-contracted, human bronchial where exhibits 390-fold...
Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid (AML). AML one of the deadliest hematopoietic malignancies, with overall 5-year survival rate 27%. The activity ENL mediated by its YEATS domain binds to acetyl and crotonyl marks on histone tails colocalizes promoters actively transcribed genes are essential for leukemia. Prior discovery TDI-11055, existing inhibitors showed vitro potency, but had not shown efficacy...
Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors transforming growth factor β-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis cluster compounds identified, which based on central pyrrole-2,4-1H-dicarboxamide scaffold, showing remarkable selectivity. A scaffold-hop corresponding imidazole resulted in increased biochemical potency. Next, X-ray...
R411 is a dual alpha4beta1-alpha4beta7 integrin antagonist under development for the treatment of chronic asthma. The objective this study was to investigate pharmacokinetics and safety its active metabolite, RO0270608, in humans. A 3-part phase I trial conducted 132 healthy volunteers: (1) 12 subjects received 200 mg as single oral dose or 100 RO0270608 an intravenous infusion 1-sequence crossover design; (2) 7 groups 10 1 doses (10-1200 mg) parallel, placebo-controlled, ascending adaptive...
Studies were performed to evaluate the contribution of intracellular Ca2+ gallbladder smooth muscle contraction under acetylcholine (ACh) or potassium stimulation. Gallbladder strips from adult guinea pigs placed in tissue baths containing N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered physiological salt solution (PSS) and set optimal length for (Lo). The results as follows, 1) A 20-min equilibration zero Ca2(+)-0.1 mM ethylene glycol-bis( beta-aminoethyl...
CRTH2 is one of the prostaglandin D₂ receptors and plays a proinflammatory role in allergic diseases. Gene expression markers whole blood induced by activation have not previously been reported. Using microarray analyses 54 675 genes, we revealed modest gene changes human stimulated vitro selective agonist, DK-PGD₂. Five genes were found to exhibit 1.5- 2.6-fold expression. The Charcot-Leyden crystal protein/galectin-10 (CLC/Gal-10) particular was consistently enhanced DK-PGD₂, as confirmed...
The inhibition of LTB(4) binding to and activation G-protein-coupled receptors BLT1 BLT2 is the premise a treatment for several inflammatory diseases. In lead optimization effort starting with leukotriene B(4) (LTB(4)) receptor antagonist (2), members series 3,5-diarylphenyl ethers were found be highly potent inhibitors receptors, varying levels selectivity depending on substitution. addition, compounds 33 38 from this have good in vitro ADME properties, oral bioavailability, efficacy after...
Tumor necrosis factor (TNF) is an inflammatory cytokine produced by many cell types which may contribute to the pathophysiology of a variety lung diseases. In this study we have used Ro 45-2081 (a soluble receptor composed human p55 TNF and heavy-chain immunoglobulin G) explore role in acute response rat intravenous injection Sephadex beads. The effects also been compared with those dexamethasone. At 24 72 h after Sephadex, there was significant increase total number leukocytes...
Experiments were designed to characterize receptor(s) that mediate nonadrenergic, noncholinergic contractions of the guinea pig hilar bronchus using selective neurokinin (NK)1 (CP 96,345) and NK2 (R396 MEN 10,376) tachykinin receptor antagonists. Left right bronchi studied as pairs in presence atropine, propranolol, phentolamine; indomethacin thiorphan. (2S, 3S)-cis-2-(diphenylmethyl)-N-(2-methoxyphe nyl)-1-azabicyclo[2,2,2]octan-3-amine selectively antagonized NK1 agonist...