gx-15-070 and Lymphoma

Augmentation and acceleration of apoptosis for cancer therapy are logical therapeutic strategies given the increasing body of data suggesting the dysregulation of control of cell death in many neoplasms. Apoptosis is particularly well studied in hematological neoplasms, thus these varied diseases present opportunities for pro-apoptotic drug development both as single agents and in combination with established therapies. Accordingly, several agents targeting function of anti-apoptotic Bcl-2 family members have entered clinical trials in the last decade and are discussed.. The pan Bcl-2 family member BH3 domain mimetic obatoclax (GX15-070) is currently under clinical evaluation in solid tumors and hematological neoplasms. This agent offers the attractive property of uniformly inhibiting all of the anti-apoptotic members of the Bcl-2 protein family. Its chemistry and preclinical development and activity are reviewed. Pharmacology, pharmacodynamics, drug resistance and clinical use of this agent in leukemias and lymphomas are discussed. The prospects for obatoclax in changing clinical practice are addressed.. Obatoclax may not prove to have dramatic single agent activity for hematological neoplasms. It seems more likely that its activity will be manifest in combination therapy with other agents, particularly cytotoxic chemotherapies. Results of ongoing studies are awaited.

Topics: Antineoplastic Agents; Apoptosis; Clinical Trials as Topic; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Indoles; Leukemia; Lymphoma; Proto-Oncogene Proteins c-bcl-2; Pyrroles

A critical regulator of the apoptotic machinery is the Bcl-2 family proteins whose over expression confers a protective effect on malignant cells against death signals of apoptosis. Cancer cells that are resistant to various anti-cancer drugs and treatment regimen are found to over express these Bcl-2 proteins such as Bcl-2, Bcl-X(L), Mcl-1, Bcl-w, and A1/Bfl1. In recent years there has been an exponential growth in the identification as well as synthesis of non-peptidic cell permeable small-molecule inhibitors (SMIs) of protein-protein interaction. The focus of this article is on inhibitors of anti-apoptotic protein Bcl-2. This review summarizes an up to date knowledge of the available SMIs, their mode of action as well as their current status in preclinical as well as clinical development.

Topics: Aniline Compounds; Animals; Apoptosis; Benzamides; Binding Sites; Biphenyl Compounds; Gossypol; Humans; Indoles; Lymphoma; Models, Molecular; Neoplasms; Nitrophenols; Piperazines; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Sulfones

Two phase I, single-agent studies were conducted to determine the dose and regimen of obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of obatoclax, respectively.. Eligible patients in both studies were adults with solid tumor or lymphoma and performance status 0-1 for whom standard therapies were not appropriate. In the GX001 study an accelerated dose titration design was initially used with subsequent cohorts of three to six patients with 40% dose increments between levels. In the GX005 study three to six patients entered at each dose level with 40% dose increments between levels.. Thirty-five patients were enrolled in studies GX001 (n = 8) and GX005 (n = 27). Clinically significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m(2) due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax MTD was 20 mg/m(2). One patient in GX005 with relapsed non-Hodgkin's lymphoma achieved partial response of 2 months' duration, and one patient with relapsed non-Hodgkin's lymphoma had stable disease for 18 months.. The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric dose-limiting toxicities at relatively low doses (MTD, 1.25 mg/m(2)). The 3-hour i.v. infusion of obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m(2)), and evidence of clinical activity was observed.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Indoles; Lymphoma; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Remission Induction

Obatoclax is a clinical stage drug candidate that has been proposed to target and inhibit prosurvival members of the Bcl-2 family, and thereby contribute to cancer cell lethality. The insolubility of this compound, however, has precluded the use of many classical drug-target interaction assays for its study. Thus, a direct demonstration of the proposed mechanism of action, and preferences for individual Bcl-2 family members, remain to be established.. Employing modified proteins and lipids, we recapitulated the constitutive association and topology of mitochondrial outer membrane Mcl-1 and Bak in synthetic large unilamellar liposomes, and measured bakdependent bilayer permeability. Additionally, cellular and tumor models, dependent on Mcl-1 for survival, were employed.. We show that regulation of bilayer permeabilization by the tBid - Mcl-1 - Bak axis closely resemblesthe tBid - Bcl-XL - Bax model. Obatoclax rapidly and completely partitioned into liposomal lipid but also rapidly exchanged between liposome particles. In this system, obatoclax was found to be a direct and potent antagonist of liposome-bound Mcl-1 but not of liposome-bound Bcl-XL, and did not directly influence Bak. A 2.5 molar excess of obatoclax relative to Mcl-1 overcame Mcl-1-mediated inhibition of tBid-Bak activation. Similar results were found for induction of Bak oligomers by Bim. Obatoclax exhibited potent lethality in a cellmodel dependent on Mcl-1 for viability but not in cells dependent on Bcl-XL. Molecular modeling predicts that the 3-methoxy moiety of obatoclax penetrates into the P2 pocket of the BH3 binding site of Mcl-1. A desmethoxy derivative of obatoclax failed to inhibit Mcl-1 in proteoliposomes and did not kill cells whose survival depends on Mcl-1. Systemic treatment of mice bearing Tsc2(+) (/) (-) Em-myc lymphomas (whose cells depend on Mcl-1 for survival) with obatoclax conferred a survival advantage compared to vehicle alone (median 31 days vs 22 days, respectively; p=0.003). In an Akt-lymphoma mouse model, the anti-tumor effects of obatoclax synergized with doxorubicin. Finally, treatment of the multiple myeloma KMS11 cell model (dependent on Mcl-1 for survival) with dexamethasone induced Bim and Bim-dependent lethality. As predicted for an Mcl-1 antagonist, obatoclax and dexamethasone were synergistic in this model.. Taken together, these findings indicate that obatoclax is a potent antagonist of membranerestricted Mcl-1. Obatoclax represents an attractive chemical series to generate second generation Mcl-1 inhibitors.

Topics: Animals; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Cell Line, Tumor; Disease Models, Animal; Doxorubicin; Drug Synergism; Humans; Indoles; Lymphoma; Membrane Proteins; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins; Pyrroles; Xenograft Model Antitumor Assays