A5017976189- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Cell death mechanisms and regulation
- Monoclonal and Polyclonal Antibodies Research
- PARP inhibition in cancer therapy
- Peptidase Inhibition and Analysis
- CAR-T cell therapy research
- Cancer therapeutics and mechanisms
- Lung Cancer Treatments and Mutations
- Cancer-related Molecular Pathways
- Regulation of Appetite and Obesity
- Lung Cancer Research Studies
- Receptor Mechanisms and Signaling
- MicroRNA in disease regulation
- Biochemical Analysis and Sensing Techniques
- Neuroblastoma Research and Treatments
- Cancer Research and Treatments
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- Chronic Myeloid Leukemia Treatments
- Lymphoma Diagnosis and Treatment
- Acute Lymphoblastic Leukemia research
- Cancer, Hypoxia, and Metabolism
- Chemical Synthesis and Analysis
AbbVie (United States)
2016-2025
UCLA Health
2024
Virginia Commonwealth University
2021-2023
Lake County
2023
VCU Massey Comprehensive Cancer Center
2021
Abbott (United States)
2003-2013
WuXi AppTec (China)
2013
Abbott Fund
2003-2012
Abbott (United Kingdom)
2012
Discovery Laboratories (United States)
2010
The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy these settings is limited by thrombocytopenia caused BCL-XL inhibition. This prompted the generation of BCL-2-selective venetoclax (ABT-199/GDC-0199), which demonstrates robust cancers but spares platelets. Navitoclax also been to enhance docetaxel preclinical models solid tumors, use this combination neutropenia. We...
Abstract The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption high-affinity protein–protein interactions, therefore designing small molecules potent enough to inhibit in cells has proven extremely challenging. Here, we describe series indole-2-carboxylic acids,...
BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, cells are sensitive to antagonists that selectively target prosurvival such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or only (ABT-199/GDC-0199/venetoclax). Resistance these three drugs is mediated by expression MCL-1. However, given the selectivity profile venetoclax it unclear whether coexpression BCL-XL also affects antitumor responses in myeloma. In cell lines (n =...
A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening structure-based design. This compound is substantially more against BCL-XL-dependent cell lines relative to our recently reported WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused mechanism-based reversible thrombocytopenia in mice inhibited H146 small lung cancer xenograft tumor growth vivo following multiple doses....
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report series MCL-1 inhibitors emanated from high throughput screening (HTS) hit progressed via iterative cycles structure-guided design. Advanced compounds this exhibited subnanomolar affinity for excellent selectivity over other proteins as well kinases GPCRs. In dependent human line, administration compound 30b rapidly induced caspase...
Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of therapy can contribute unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor induced into doxorubicin or etoposide give rise viable tumors vivo. We further demonstrate sensitivity these senescent the senolytic ABT-263 (navitoclax), therefore providing a "two-hit" approach eliminate persist after exposure...
Abstract Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to lack of druggable targets. Experimental Design: We used high-throughput drug screen identify venetoclax-sensitive subpopulation and validated the findings with multiple patient-derived xenografts SCLC. Results: Our consisting very large...
Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted for survival are now being targeted therapeutically. For example, navitoclax, BCL-2/BCL-XL/BCL-W inhibitor, is currently in phase I/II clinical trials numerous malignancies. However, related member, MCL-1, limits efficacy navitoclax and other chemotherapeutic agents. In present study, we...
Abstract As a population, non-Hodgkin’s lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; High ) are exquisitely sensitive to navitoclax or B-cell protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some remain resistant either agent. Here we show that MCL-1-specific A-1210477 sensitizes these navitoclax. Chemical segregation of this synergy with BCL-2-selective venetoclax BCL-X L -selective A-1155463 indicated...
High-throughput screening identified hypersensitivity of neuroblastomas to H3K27 demethylation inhibition.
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported A-1155463 using structure-based drug design. Key design elements included rigidification pharmacophore introduction sp3-rich moieties capable generating highly productive interactions within key P4 pocket BCL-XL. A-1331852 has since been used as...
MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays critical role in tumor maintenance and survival can act as resistance factor to multiple anticancer therapies. Herein, we describe the generation characterization of highly potent selective inhibitor ABBV-467 present findings from first-in-human trial included patients with relapsed/refractory myeloma (NCT04178902).Binding human was assessed cell lines. The ability induce growth inhibition investigated xenograft models acute...
A highly potent and selective DGAT-1 inhibitor was identified used in rodent models of obesity postprandial chylomicron excursion to validate inhibition as a novel approach for the treatment metabolic diseases. Specifically, compound 4a conferred weight loss reduction liver triglycerides when dosed chronically DIO mice depleted serum following lipid challenge dose-dependent manner, thus, reproducing major phenotypical characteristics DGAT-1−/− mice.
MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance enabling resistance to anti-tumorigenic agents including BCL-2 selective inhibitor venetoclax. The expression maintained via P-TEFb-mediated transcription, where kinase CDK9 a critical component. Consequently, we developed series potent small-molecule inhibitors CDK9, exemplified by orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules have...
// Juraj Bodo 1 , Xiaoxian Zhao Lisa Durkin Andrew J. Souers 2 Darren C. Phillips Mitchell R. Smith 3 Eric D. Hsi Department of Laboratory Medicine, Robert Tomsich Pathology and Medicine Institute, Cleveland Clinic, Cleveland, OH, USA Oncology Discovery, AbbVie, Inc., Chicago, IL, Hematology Medical Oncology, Taussig Cancer Correspondence to: Hsi, email: hsie@ccf.org Keywords: venetoclax, resistance, follicular lymphoma Received: April 15, 2016 Accepted: August 10, Published: September 20,...
[reaction: see text] Microwave irradiation strongly accelerates the rhodium-catalyzed intramolecular coupling of a benzimidazole C-H bond to pendant alkenes. The cyclic products were formed in moderate excellent yields with reaction times less than 20 min. Additionally, use microwave allowed reactions be performed without any solvent purification and minimal precautions exclude air.
ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-xL Bcl-2. This class putative anticancer agents invariantly contains an acylsulfonamide core. We have designed synthesized a series novel quinazoline-based Bcl-2 that contain heterocyclic alternative to acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines presence 10% serum. comprises first successful demonstration quinazoline sulfonamide...