A5039510645- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Cell death mechanisms and regulation
- Ubiquitin and proteasome pathways
- Melanoma and MAPK Pathways
- Cancer, Hypoxia, and Metabolism
- RNA Interference and Gene Delivery
- Lipid Membrane Structure and Behavior
- Autophagy in Disease and Therapy
- Chromatin Remodeling and Cancer
- Metalloenzymes and iron-sulfur proteins
- Enzyme Structure and Function
- ATP Synthase and ATPases Research
- Computational Drug Discovery Methods
- Phagocytosis and Immune Regulation
- Metabolism, Diabetes, and Cancer
- Advancements in Semiconductor Devices and Circuit Design
- Click Chemistry and Applications
- Erythrocyte Function and Pathophysiology
- Machine Learning in Bioinformatics
- Nanoparticle-Based Drug Delivery
- Metal-Catalyzed Oxygenation Mechanisms
- Mitochondrial Function and Pathology
- Lymphoma Diagnosis and Treatment
- CAR-T cell therapy research
C4 Therapeutics (United States)
2021-2023
University of Massachusetts Amherst
2014-2019
Zinc is emerging as a widely used and important biological regulatory signal. Cellular zinc levels are tightly regulated by complex array of importers exporters to control processes such apoptotic cell death. While caspase inhibition has been reported previously, the constants were too weak suggest critical role for zinc-mediated inhibition. In this work, we have adopted method assessing available zinc. This allowed assessment accurate caspases, caspase-3, -6, -7, -8. Each these caspases...
The field of targeted protein degradation (TPD) has grown exponentially over the past decade with goal developing therapies that mark proteins for destruction leveraging ubiquitin-proteasome system. One common approach to achieve TPD is employ a heterobifunctional molecule, termed as degrader, recruit target interest E3 ligase machinery. resultant generation an intermediary ternary complex (target-degrader-ligase) pivotal in process. Understanding geometry offers valuable insight into...
Abstract Introduction: The chromatin factor BRD9 is a genetic dependency in some cancers, often referred to as SMARCB1-perturbed cancers. Two types of alterations result SMARCB1 perturbation: SS18-SSX gene fusion and loss-of-function mutations. In synovial sarcoma, rare aggressive soft tissue malignancy comprising approximately 10% all sarcomas, the presence drives disruption function leads synthetic lethal dependence on BRD9. SMARCB1-null solid tumors, for example malignant rhabdoid tumors...
Conjugation of biologically active proteins to polymeric materials is great interest in the treatment cancer and other diseases protein deficiency. The conjugation such biomacromolecules challenging both due their hydrophilicity propensity denature under non-native conditions. We describe a novel reactive self-assembly approach "wrap" with polymers, simultaneously protecting its delicate folded state silencing enzymatic activity. This has been demonstrated using caspase-3, an...
Therapeutic biologics have various advantages over synthetic drugs in terms of selectivity, their catalytic nature, and, thus, therapeutic efficacy. These properties offer the potential for more effective treatments that may also overcome undesirable side effects observed due to off-target toxicities small molecule drugs. Unfortunately, systemic administration is challenging cellular penetration, renal clearance, and enzymatic degradation difficulties. A delivery vehicle can these challenges...
In addition to the therapeutic applicability of targeted protein degradation (TPD), modality also harbors unique properties that enable development innovative chemical biology tools interrogate complex biology. TPD offers an all-chemical strategy capable potent, durable, selective, reversible, and time-resolved control levels a given target in both vitro vivo contexts. These are particularly well-suited for enabling precise perturbation gene understand its biology, identify...
Abstract The BRAF kinase is a critical node in the MAPK signaling pathway and mutated approximately 8% of human cancers including melanoma (~60%), thyroid lung adenocarcinoma (~10%). most common mutation V600E (Class I), occurring half malignant melanomas. This hyperactivates ERK signals as RAF inhibitor-sensitive monomer. inhibitors vemurafenib, dabrafenib encorafenib have produced impressive responses V600X patients, however resistance usually emerges within year, RAS mutation, BRAFV600E...
Abstract The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated ~8% of all human cancers including melanoma (~60%), thyroid lung adenocarcinoma (~10%). most common mutation V600E (Class I), which found >70% these cancers. Despite clinical success approved small molecule inhibitors (vemurafenib, dabrafenib encorafenib), this remains an area unmet medical need because nearly patients progress, due to either primary or acquired resistance. A bifunctional...
Immunomodulatory drugs, such as pomalidomide and lenalidomide are approved for the treatment of multiple subtypes NHL. These drugs induce an interaction between Ikaros family zinc finger proteins 1 3 (IKZF1/3) cereblon (CRBN), E3 ligase, resulting in IKZF1/3 degradation. Clinically, immunomodulatory active single agents or when used combination with several classes targeted therapies, both first line relapsed/refractory NHL subtypes. We previously described preclinical characterization...
Abstract Introduction Ikaros family zinc finger protein 1 and 3 (IKZF1/3) are essential transcription factors (TF) for terminal differentiation of B T cells. Depletion IKZF1/3 in MM cells inhibits growth, confirming their dependency on IKZF1/3. IMiDs (lenalidomide[len], pomalidomide[pom]) effective therapies treatment promote degradation via interaction with CRL4-CRBN E3 ligase. Most patients treated len or pom eventually develop progressive disease due to acquired resistance, underscoring...
Introduction: Ikaros family zinc finger protein 1 and 3 (IKZF1/3) are essential transcription factors (TF) for differentiation of B T lymphocytes. IMiDs (e.g. pomalidomide (pom)) degrade IKZF1/3 via interaction with the cereblon (CRBN) E3 ligase have shown promise in NHL. Preclinical data suggest improvements degraders may lead to enhanced efficacy. CFT7455 is a novel degrader optimized high affinity CRBN binding degradation, resulting downregulation interferon regulatory factor 4 (IRF4),...
Abstract The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated ~8% of all human cancers including melanoma (~60%), thyroid lung adenocarcinoma (~10%). most common mutation V600E (Class I), which found >70% these cancers. Despite clinical success approved small molecule inhibitors (vemurafenib, dabrafenib encorafenib), this remains an area unmet medical need because nearly patients progress, due to either primary or acquired resistance. A bifunctional...
Abstract Introduction: Ikaros family zinc finger protein 1 and 3 (IKZF1/3) are essential transcription factors (TF) for terminal differentiation of B T cells. Depletion IKZF1/3 inhibits the growth multiple myeloma (MM) cells, confirming their dependency on IKZF1/3. IMiDs (lenalidomide, pomalidomide) effective therapies treatment MM promote degradation via interaction with CRL4-CRBN E3 ligase. However, most patients treated lenalidomide or pomalidomide eventually develop progressive disease...
Caspases and kinases are caught in a web of complex interplay, the battle between them tips scale toward cell death or survival. Each caspase is phosphorylated different locations by kinases, which leads to differential regulation for each caspase. For example, caspase‐9, an initiator apoptosis, extensively on all its domains multiple kinases. In contrast, single phosphorylation site has been identified caspase‐6. Our work seeks understand molecular details mechanisms inhibition activation...
Caspases, the cysteine proteases that execute apoptosis, are tightly regulated via phosphorylation by a series of kinases. Although all apoptotic caspases work in concert to promote different kinases regulate individual caspases. Several sites caspase‐7 and −9 have been reported, but without knowing molecular details, it has impossible exploit or control these complex interactions, which normally prevent unwanted proliferation. This provides new mechanisms for phosphorylation‐based both...