A5061037172- Cancer therapeutics and mechanisms
- Nuclear Receptors and Signaling
- Acute Myeloid Leukemia Research
- HIV/AIDS drug development and treatment
- DNA Repair Mechanisms
- Cancer-related Molecular Pathways
- Cytokine Signaling Pathways and Interactions
- Bioactive Compounds and Antitumor Agents
- Cancer Genomics and Diagnostics
- Chronic Lymphocytic Leukemia Research
- DNA and Nucleic Acid Chemistry
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Synthesis of Tetrazole Derivatives
- Click Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Carbohydrate Chemistry and Synthesis
- Radiopharmaceutical Chemistry and Applications
- Carcinogens and Genotoxicity Assessment
- Metal complexes synthesis and properties
- Chronic Myeloid Leukemia Treatments
- Synthesis and Reactivity of Heterocycles
- Synthesis and Biological Evaluation
- Glycogen Storage Diseases and Myoclonus
- Chemokine receptors and signaling
Revolution Medicines (United States)
2024-2025
Maze (United States)
2024
Menlo School
2022
Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role energy homeostasis and has been proposed as therapeutic target multiple storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors this enzyme. Here, we report preclinical characterization MZ-101, small molecule that potently inhibits GYS1 vitro vivo without inhibiting GYS2, related isoform essential for synthesizing liver glycogen....
Abstract Activating RAS mutations are among the most common drivers of human cancers. Upregulation RAS-MAPK signaling leads to sustained cell proliferation and immune escape via tumor cell-intrinsic modulation molecules crosstalk with microenvironment (TME). Major epithelial tumors harboring G12D variant, oncogenic KRAS mutation, remain an unmet medical need. The investigational agent RMC-9805, a RAS(ON) G12D-selective covalent inhibitor, exhibits potent antitumor activity in xenograft...
Abstract Colorectal cancer (CRC) is the third most commonly diagnosed in United States. About 40% of colorectal cancers have mutations KRAS, with KRAS G12D representing largest population. Targeted therapies, as well immune checkpoint inhibitor limited efficacy monotherapies for patients microsatellite stable (MSS) CRC. However, recent clinical evidence BRAF mutant MSS CRC showed that inhibitors combination MEK or EGFR and anti-PD-1 resulted significantly longer overall survival a higher...
DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, orally bioavailable, highly potent, and selective pharmacologic inhibitor DNA-PK activity, for treatment human cancerous malignancies. ZL-2201 demonstrated greater selectivity effectively inhibited autophosphorylation concentration- time-dependent manner....
Abstract Mutant KRAS is present in more than 80% pancreatic cancer, promotes cancer cell survival, and protects cells from immune recognition attack. We have shown that inhibitors of the active state RAS (RAS(ON)) promote neoantigen synergize with immunotherapy preclinical immunogenic models. 1 evaluated impact RMC-6236, an investigational RASMULTI(ON) inhibitor on anti-tumor activity tumor microenvironment (TME) remodeling two congenic KRASG12D/+ GEMM-derived PDAC models resistant to...
<h3>Background</h3> PDAC is a non-immunogenic neoplasm presenting with low tumor mutational burden and developing multiple mechanisms of immune evasion. To date, trials combining the standard-of-care, chemotherapy, immunotherapy have failed to demonstrate clinically meaningful benefit for patients. Mutant KRAS main driver carcinogenesis in PDAC, present 92% pancreatic cancers. Oncogenic RAS signaling sustains cell proliferation orchestrates escape within tumor. Therefore, addition...
Abstract DNA-damaging poisons and replicative stress commonly result in increased double-strand breaks (DSBs) tumor cells. Non-homologous end joining (NHEJ), driven by the enzymatic function of DNA-PK, is one critical pathways employed to repair such DSBs. Inhibition DNA-PK kinase activity impairs NHEJ, potentiates agents, inhibits survival cells incapable repairing DSBs via other means, including homologous recombination (HR). We have developed an orally bioavailable, highly potent,...
Abstract Despite the promise of immunotherapy for cancer treatment, nearly 80% patients fail to respond checkpoint inhibitor (CPI) therapy. Regulatory T cells (Tregs), which inhibit immune responses in tumor microenvironment via multiple suppressive mechanisms, have been proposed play a key role those who are not responding CPI Therefore, targeted depletion Tregs should promote more effective antitumor immunity. CCR8 is chemokine receptor that selectively expressed on highly activated human...
<p>ZL-2201 anti-proliferative IC50s and ATM mutational VAF status</p>
<p>Phenotypic effects of combining ZL-2201 and Doxorubicin</p>
<p>ZL-2201 treatment exhibits potent antitumor efficacy in vivo.</p>
<p>ZL-2201 treatment exhibits potent antitumor efficacy in vivo.</p>
<p>ZL-2201 reduces DNA damage-induced MCM2 phosphorylation (Ser108).</p>
<p>Kinetics of Bleomycin-induced DNA-PK phosphorylation by ZL-2201</p>
<p>ZL-2201 anti-proliferative IC50s and ATM mutational VAF status</p>
<div>Abstract<p>DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response (DDR) pathway, plays an instrumental role in repairing double-strand breaks (DSBs) induced by DNA-damaging poisons. We evaluate ZL-2201, orally bioavailable, highly potent, and selective pharmacological inhibitor DNA-PK activity, for treatment human cancerous malignancies. ZL-2201 demonstrated greater selectivity effectively inhibited autophosphorylation...
<p>Synthesis of ZL-2201</p>
<div><p>DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, orally bioavailable, highly potent, and selective pharmacologic inhibitor DNA-PK activity, for treatment human cancerous malignancies. ZL-2201 demonstrated greater selectivity effectively inhibited autophosphorylation concentration-...
<p>Phenotypic effects of combining ZL-2201 and Doxorubicin</p>
<p>Synthesis of ZL-2201</p>
<p>ZL-2201 reduces DNA damage-induced MCM2 phosphorylation (Ser108).</p>
<p>Kinetics of Bleomycin-induced DNA-PK phosphorylation by ZL-2201</p>