A5039608468- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- Amino Acid Enzymes and Metabolism
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- Catalytic Alkyne Reactions
- Retinal Diseases and Treatments
- Complement system in diseases
- Synthetic Organic Chemistry Methods
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Immune Cell Function and Interaction
- Synthesis and Reactions of Organic Compounds
- Histone Deacetylase Inhibitors Research
- Catalytic Cross-Coupling Reactions
- Erythrocyte Function and Pathophysiology
- IL-33, ST2, and ILC Pathways
- Carbohydrate Chemistry and Synthesis
- Molecular Sensors and Ion Detection
- Synthesis and Characterization of Heterocyclic Compounds
- Synthesis and Biological Evaluation
- Hidradenitis Suppurativa and Treatments
- Cytokine Signaling Pathways and Interactions
- Angiogenesis and VEGF in Cancer
Akebia Therapeutics (United States)
2017-2024
Woomera Therapeutics
2022-2024
RaNA Therapeutics (United States)
2021
Novartis (United States)
2013-2020
Discovery Institute
2011-2013
Novartis Institutes for BioMedical Research
2012-2013
Novartis (Switzerland)
2012-2013
Massachusetts Institute of Technology
2010
Imperial College London
2004-2005
King's College London
2003
Significance Enzymes of the folate cycle are among most consistently overexpressed proteins in cancer. Whereas multiple clinical agents inhibit thymidylate synthase, no current drugs target incorporation one-carbon into folates via serine hydroxymethyltransferase (SHMT). Using genetics, we show that cancer cells require SHMT to generate tumors. We then describe small-molecule inhibitors, and they block growth many human cells, with B-cell lymphomas particularly sensitive inhibition. find...
A hallmark of metastasis is the adaptation tumor cells to new environments. Metabolic constraints imposed by serine and glycine-limited brain environment restrict metastatic growth. How metastases overcome these growth-prohibitive conditions poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes rate-limiting step glucose-derived synthesis, a major determinant in multiple human cancer types preclinical models. Enhanced synthesis proved...
Abstract Many tumour cells show dependence on exogenous serine and dietary glycine starvation can inhibit the growth of these cancers extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression de novo synthesis pathway (SSP) enzymes or activation oncogenes that drive synthesis. Here we inhibition PHGDH, first step SSP, cooperates with depletion one-carbon metabolism cancer growth. In vitro, PHGDH combined leads a...
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead complement-driven nephropathies. Here we describe discovery highly potent, reversible, selective small-molecule inhibitor factor B, serine protease that drives central amplification loop AP. Oral administration prevents KRN-induced arthritis in...
Abstract Toll-like receptor–driven and interleukin-1 (IL-1) inflammation mediated by IL-1 receptor–associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied a randomized, double-blind, placebo-controlled phase 1 trial where primary objective safety tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics clinical activity patients with moderate to severe HS...
A novel approach for N-arylation utilizing aryl carboxylic acids as stable, inexpensive and widely available arylating reagents was developed. Employing a simple copper(II)–phenanthroline catalyst system, several benzoic bearing suitable ortho-substitutions undergo decarboxylative C–N cross-coupling effectively with various N-nucleophiles.
Developing therapies for the activated B-cell like (ABC) subtype of diffuse large lymphomas (DLBCL) remains an area unmet medical need. A subset ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling its catalytic scaffolding functions, necessitating complete removal this escape mechanisms therapeutic...
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both which have been implicated in multiple autoimmune conditions. Hence, blocking activity IRAK4 represents attractive approach for treatment diseases. The this serine/threonine dependent on its scaffolding activities; thus, degradation a potentially superior to inhibition. Herein, we detail exploration structure-activity relationships that ultimately led identification...
A convenient and efficient flow method for Ullmann condensations, Sonogashira couplings, decarboxylation reactions using a commercially available copper tube reactor (CTFR) is described. The heated CTFR effects these transformations without added metals (e.g., Pd), ligands, or reagents, in greater than 90% yield most cases examined.
The alternative pathway (AP) of the complement system is a key contributor to pathogenesis several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. serine protease factor B (FB) node in AP integral formation C3 C5 convertase. Despite prominent role FB AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we...
<div>Abstract<p>Murine double minute 2 (MDM2) is an E3 ligase that inhibits the tumor suppressor protein p53. Clinical trials employing small-molecule MDM2/p53 interaction inhibitors have demonstrated limited activity, underscoring unmet need for a better approach to target MDM2. KT-253 highly potent and selective heterobifunctional degrader overcomes MDM2 feedback loop seen with induces apoptosis in range of hematologic solid lines. A single intravenous dose triggered rapid...
<p>Supplemental Table 1: Cell lines and reagents</p>
<p>Supplemental Table 2: Genes and TaqMan Gene Expression Assay IDs used for RT-qPCR assays</p>
<p>Supplemental Figure 2: Targeted proteomics analysis of MDM2 levels in MV4;11 AML cells shows that 150 nM KT 253 can achieve degradation within 1 hour posttreatment.</p>
<p>Supplemental Figure 1: Chemical structures of (A) Compound 1, a KT 253 analog that lacks ability to engage cereblon (CRBN), (B) 2, the warhead engages MDM2, and (C) DS-3032, small-molecule MDM2/p53 interaction inhibitor.</p>
<p>Supplemental Table 4: KT-253 shows potent growth inhibition and caspase activation across a panel of p53 wild-type hematologic cell lines.</p>
<p>Supplemental Figure 7: A single dose of KT 253 shows strong single-agent activity in a venetoclax resistant patient-derived AML model.</p>
<p>Supplemental Figure 5: A single dose of KT-253 more robustly induces p53 targets compared with exposure matched weekly dosing regimen.</p>
<p>Supplemental Table 3: KT-253 shows picomolar growth inhibition potency compared with other MDM2 small molecule inhibitors.</p>