A5090020654- Protein Degradation and Inhibitors
- Prostate Cancer Treatment and Research
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Histone Deacetylase Inhibitors Research
- Wnt/β-catenin signaling in development and cancer
- Cancer-related gene regulation
- CAR-T cell therapy research
- Cytokine Signaling Pathways and Interactions
- Enzyme function and inhibition
- Epigenetics and DNA Methylation
- Cancer Immunotherapy and Biomarkers
- PI3K/AKT/mTOR signaling in cancer
- Immune Cell Function and Interaction
- Melanoma and MAPK Pathways
- Synthetic Organic Chemistry Methods
- Crystallization and Solubility Studies
- Peptidase Inhibition and Analysis
- Protein Kinase Regulation and GTPase Signaling
- X-ray Diffraction in Crystallography
- Acute Myeloid Leukemia Research
- Ion Channels and Receptors
- Mechanisms of cancer metastasis
- Crystallography and molecular interactions
- interferon and immune responses
Genentech
2012-2015
Oslo University Hospital
2013
Czech Academy of Sciences, Institute of Molecular Genetics
2013
Czech Academy of Sciences
2013
Bayer (United States)
2004-2007
University of Alberta
1995-2001
Columbia University
1998
Kettering University
1998
Acetylation of histone H3 at lysine 27 is a well-defined marker enhancer activity. However, the functional impact this modification enhancers poorly understood. Here, we use chemical genetics approach to acutely block function cAMP response element binding protein (CREB) (CBP)/P300 bromodomain in models hematological malignancies and describe consequent loss H3K27Ac specifically from enhancers, despite continued presence CBP/P300 chromatin. Using dissect role identify critical for production...
Abstract Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin–mediated signaling. However, continued requirement Wnt/β-catenin signaling for tumor progression in the context acquired KRAS and other is less well-established. To attenuate tumors, we have developed potent specific small-molecule tankyrase inhibitors, G007-LK G244-LM, that reduce preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization....
Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as "readers" ultimately determine functional outcome of post-translational modification. Because initial discovery selective BET inhibitors have helped define family oncology and inflammation, bromodomains continued to garner most attention any other bromodomain. More recently, non-BET bromodomain are potent been disclosed for ATAD2, CBP, BRD7/9,...
Despite the development of effective therapies, a substantial proportion asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, rodents, TRPA1 is involved induction airway inflammation hyperreactivity. Here, discovery early clinical GDC-0334, highly potent, selective, orally bioavailable antagonist, described. GDC-0334 inhibited function on smooth...
Resistance invariably develops to antiandrogen therapies used treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required maintain growth of cancer. To exploit this vulnerability, developed a novel small-molecule inhibitor bromodomain blocks cancer in vitro and vivo Molecular dissection consequences drug treatment revealed critical role histone acetylation activity...
TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack expression indicate the IFN-α, IL-23 pathways, but not IL-6 or IL-10 are compromised. In contrast, there have been few role primary human cells. A genetic mutation at tyk2 locus results single patient has linked defects suggesting broad for cytokine responses. this article, we used panel novel potent small-molecule...
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent highly selective inhibitors effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing N-methyl group were designed directing toward conserved water pocket, two distinct binding conformations then observed. either...
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort explore the potential therapeutic implications selectively targeting bromodomains, we set out identify a CBP/EP300 bromodomain inhibitor that was potent both vitro target engagement assays selective over other members family. Reported here is series cell-potent probes derived from fragment screening hit...
Inhibition of the bromodomain transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed vivo chemical tool 1 (GNE-272) for CBP that was moderately potent and selective over BRD4(1). In pursuit a more inhibitor, we used structure-based design. Constraining aniline into tetrahydroquinoline motif maintained potency increased selectivity 2-fold. Structure–activity relationship studies coupled with further design targeting LPF...
Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role hematopoiesis was identified as dependency factor leukemia stem cell populations. Therefore, we investigated consequences inhibiting panel lines representing all acute myelogenous (AML) subtypes using selective, reversible irreversible small-molecule inhibitors. Cell models AML, CML, T-ALL were...
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as polymodal sensor for exogenous and endogenous stimuli, has been implicated neuropathic pain respiratory disease. Herein, we describe optimization of potent, selective, orally bioavailable TRPA1 small molecule antagonists with strong vivo target engagement rodent models. Several lead molecules preclinical single- short-term repeat-dose toxicity...
Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with molecule 3. We used structure-based design discover 2,6-dichloro-4-cyanophenyl (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved potency JAK1 JAK2 selectivity relative Further eventually led compound 37 that showed good enzyme interleukin-12 (IL-12) cell potency, as well acceptable cellular excellent oral exposure in mice. When...
Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that involved in several biological processes and plays central role the ubiquitin-mediated degradation misfolded proteins. VCP an ubiquitously expressed, highly abundant has been found overexpressed many tumor types, sometimes associated with poor prognosis. In this respect, recently received great deal attention potential new target for cancer therapy. paper, discovery structure-activity relationships...
The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest discovering selective inhibitors for use treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor Jak2. Optimization lead compounds 7a-b and 8 this chemical series activity against Jak2, selectivity other Jak family kinases, good vivo pharmacokinetic properties 7j. In SET2 xenograft model that...
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target much recent interest in cancer and immune system regulation. A co-crystal structure ligand-efficient screening hit CBP guided initial design targeting LPF shelf, ZA loop, acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify more potent analogue. Optimization permeability microsomal stability subsequent improvement mouse hepatocyte afforded 59 (GNE-272,...
Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator H3K27 acetylation (H3K27ac) MDSCs across promoters enhancers pro-tumorigenic target genes. In preclinical models, vivo administration CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral attenuates established growth immunocompetent tumor-bearing mice, well...
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as polymodal sensor for exogenous and endogenous stimuli has generated widespread interest target inhibition due to its implication neuropathic pain respiratory disease. Herein, we describe optimization of series potent, selective, orally bioavailable TRPA1 small molecule antagonists, leading discovery novel tetrahydrofuran-based linker....
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTA Concise Total Synthesis of Dysidiolide through Application a Dioxolenium-Mediated Diels−Alder ReactionSteven R. Magnuson, Laura Sepp-Lorenzino, Neal Rosen, and Samuel J. DanishefskyView Author Information Department Chemistry, Columbia University Havemeyer Hall, New York, 10027 Laboratories for Bioorganic Chemistry Molecular Oncogenesis Sloan-Kettering Institute Cancer Research 1275 York Avenue, Box 106, 10021 Cite this: Am. Chem. Soc....
Mitogen-activated protein kinase 4 (MAP4K4) is a serine/threonine implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like compounds. efforts eventually led us focus on pyridopyrimidine series, from which...