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Principal Investigator: Marina Y Konopleva
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $480,430
Funding agency: National Cancer Institute
Targeting the anti-apoptotic Bcl-2 family proteins is a promising therapeutic strategy for cancer and has been
validated by the FDA approval of the Bcl-2 selective inhibitor, venetoclax, for the treatment of chronic lymphocytic
leukemia (CLL) and acute myeloid leukemia (AML). Given the well-documented importance of Bcl-xL to many
types of cancers, including most T-cell acute lymphoblastic leukemia (T-ALL), and its contribution to drug
resistance, Bcl-xL has become one of the best validated cancer targets. Unfortunately, the on-target and dose-
limiting platelet toxicity associated with the inhibition of Bcl-xL has prevented the use of Bcl-xL inhibitors in the
clinic. To circumvent this toxicity, we have applied the Proteolysis Targeting Chimera (PROTAC) technology to
design small-molecules that target Bcl-xL to E3 ligases for degradation. Our hypothesis is that Bcl-xL degrading
PROTACs (named as Bcl-Ps) designed to recruit an E3 ligase that is minimally expressed in platelets for the
targeted degradation of Bcl-xL will have reduced platelet toxicity and improved antitumor activity compared with
their corresponding Bcl-xL inhibitors. This hypothesis is supported by our strong preliminary results, including in
vivo efficacy data in T-ALL patient-derived xenograft (PDX) mouse models and other tumor xenograft mouse
models. In addition, our Bcl-Ps are also potent senolytic agents that can selectively kill senescent cells (SnCs),
because SnCs also rely on Bcl-xL for survival. Clearance of chemotherapy-induced SnCs is considered as a
novel strategy to prevent or reduce many short- and long-term adverse effects of the chemotherapeutic drugs,
as well as cancer relapse and metastasis. Collectively, these findings suggest that Bcl-Ps are superior to
conventional Bcl-xL inhibitors as anticancer agents. The goal of this application is to: (1) optimize Bcl-Ps for
improved potency, selectivity, drug-like properties, and in vivo efficacy; (2) evaluate the new Bcl-Ps through a
series of in vitro and in vivo assays; and (3) evaluate the preclinical efficacy of lead Bcl-Ps in T-ALL PDX models.
Upon completion of this project, we aim to produce Bcl-Ps amenable to further evaluation in clinical trials for T-
ALL, an aggressive leukemia that currently has no targeted therapies.
Terms: <14-Hydroxydaunomycin><AML - Acute Myeloid Leukemia><ASP-1><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Acute T Cell Leukemia><Acute T-Cell Lymphoblastic Leukemia><Acute T-Cell Lymphocytic Leukemia><Acute T-Lymphocytic Leukemia><Adriamycine><Adverse effects><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Apoptosis><Apoptosis Pathway><Apoptotic><Asparaginase II><Asparagine Deaminase><Assay><B cell lymphoma 2><B-Cell CLL><B-Cell CLL/Lymphoma 2 Gene><B-Cell Chronic Lymphocytic Leukemia><B-Cell Chronic Lymphogenous Leukemia><B-Cell Chronic Lymphoid Leukemia><B-Cell Lymphocytic Leukemia><B-Lymphocytic Leukemia><B-cell lymphoma-extra large><B-cell lymphoma/leukemia-2><BCL-XL><BCL2><BCL2 gene><BCL2-Like 1><BCL2-Related Gene><BCL2-Related Protein, Long Isoform><BCL2-Related Protein, Short Isoform><BCL2L1><BCL2L1 gene><BCLX><BCLXL><BCLXS><Bcl-2><Bcl-XL protein><Bioassay><Biological Assay><Blood Platelets><Body Tissues><Cancer Drug><Cancer Relapse><Cancer Treatment><Cancers><Chemoresistance><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chronic B-Lymphocytic Leukemia><Chronic Lymphatic Leukemia><Chronic Lymphoblastic Leukemia><Chronic Lymphocytic Leukemia><Chronic Lymphogenous Leukemia><Clinic><Clinical Trials><Colaspase><Coupled><Cytometry><Data><Dependence><Development><Dexamethasone><Dose Limiting><Doxorubicin><Doxorubicina><Drug Kinetics><Drug resistance><Drugs><E3 Ligase><E3 Ubiquitin Ligase><Elspar><Evaluation><Exhibits><Formulation><Goals><Human><Hydrogen Oxide><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><In Vitro><In vivo analysis><Kidrolase><L asparagine amidohydrolase><L-ASP><L-Asparaginase><Lcf-ASP><Lead><Leukemia Acute Lymphoblastic Chemotherapy><Leurocristine><Ligands><MCL-1><MCL1><MCL1 gene><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Marrow platelet><Mediating><Medication><Metabolic Protein Degradation><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modern Man><Murine><Mus><Names><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><PDX model><Patient derived xenograft><Patients><Pb element><Pharmaceutical Preparations><Pharmacokinetics><Platelets><Play><Position><Positioning Attribute><Precursor T Lymphoblastic Leukemia><Programmed Cell Death><Property><Protac><Protein Family><Protein Turnover><Proteins><Proteolysis targeting chimeric><Refractory><Regulatory Protein Degradation><Relapse><Research><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Serasa><Series><Specificity><T-Cell Type Acute Leukemia><T-lineage acute lymphoblastic leukemia><Techniques><Technology><Testing><Therapeutic><Thrombocytes><Thrombocytopenia><Thrombopenia><Tissues><Toxic effect><Toxicities><Treatment Efficacy><Tumor-Specific Treatment Agents><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Vincristine><Vincrystine><Water><acute granulocytic leukemia><acute lymphoblastic leukemia Chemotherapy><acute myeloid leukemia><analog><anti-cancer><anti-cancer drug><anti-cancer therapy><asparaginase><bcl-2 Genes><bcl-x(L) protein><bcl-xlong protein><cancer cell><cancer metastasis><cancer therapy><cancer type><cancer-directed therapy><ced9 homolog><chemo/radiation therapy><chemoresistant><chemotherapy><chemotherapy and radiotherapy><chemotherapy resistance><chemotherapy resistant><chronic lymphoid leukemia><clinical applicability><clinical application><clinical relevance><clinically relevant><design><designing><determine efficacy><developmental><drug discovery><drug resistant><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><heavy metal Pb><heavy metal lead><improved><in vitro Assay><in vivo><in vivo evaluation><in vivo testing><inhibitor><innovate><innovation><innovative><intervention efficacy><leukemia><malignancy><mouse model><murine model><myeloid cell leukemia 1><myeloid cell leukemia sequence 1><myeloid leukemia cell differentiation protein><name><named><naming><neoplasm/cancer><new approaches><novel><novel approaches><novel strategies><novel strategy><oxovincaleukoblastine><patient derived xenograft model><pre-clinical efficacy><preclinical efficacy><prevent><preventing><protein degradation><proteolysis targeting chimera><radiation or chemotherapy><recruit><resistance to Drug><resistant><resistant to Drug><scale up><senescence associated secretome><senescence associated secretory phenotype><senescent cell><senolytics><small molecule><social role><standard of care><success><targeted cancer therapy><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><tumor><tumor cell metastasis><tumor initiation><tumor xenograft><ubiquitin-protein ligase>