Targeting apoptosis via chemical design of Bcl-2 antagonists

通过 Bcl-2 拮抗剂的化学设计靶向细胞凋亡

• 批准号: 8606735
• 负责人: Maurizio Pellecchia
• 金额: $ 38.07万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606735
• 关键词: Affect; Anisotropy; Antineoplastic Agents; Antisense Oligonucleotides; Apoptosis; Apoptosis Regulator; Apoptotic; Attention; Augmerosen; BCL2 gene; BH3 Domain; Behavior; Benzamides; Benzoic Acids; Binding; Biological Assay; Biological Factors; Blood; CH3OCF2CH(CF3)OCH2F; Calorimetry; Cancer cell line; Cell Culture Techniques; Cell Death; Cell Death Inhibition; Cells; Chemical Structure; Chemicals; Chronic Lymphocytic Leukemia; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Combined Modality Therapy; Coupled; Cytotoxic agent; Data; Defect; Development; Dimerization; Docking; Dose; Drug Formulations; Drug Targeting; Ensure; Equilibrium; Evaluation; Family; Family member; Fluorescence Polarization; Genes; Goals; Gossypol; Homeostasis; Human; In Vitro; Investigation; Ketones; Laboratories; Lead; Lymphoma; MCL1 protein; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Mediating; Methods; Michigan; Monitor; Multiple Myeloma; Mus; NMR Spectroscopy; Nature; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nuclear Magnetic Resonance; Oblimersen; Outcome; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Play; Production; Property; Protein Binding; Protein Family; Proteins; Radiation; Radiation therapy; Radioresistance; Regulation; Reporting; Research; Research Design; Research Methodology; Research Personnel; Resistance; Role; Route; Scheme; Signal Pathway; Signal Transduction; Solid; Structure; Surface; Techniques; Testing; Therapeutic; Time; Titrations; Toxic effect; Tumorigenicity; Universities; Up-Regulation; Validation; Work; Xenograft Model; Xenograft procedure; antitumor agent; apogossypol; base; biophysical techniques; cancer cell; cancer therapy; chemotherapy; comparative efficacy; cytotoxicity; design; dosage; drug candidate; drug development; drug discovery; experience; improved; in vitro Assay; in vivo; inhibitor/antagonist; innovation; interdisciplinary approach; interest; leukemia; melanoma; member; mouse model; novel; pharmacokinetic characteristic; preclinical study; pro-apoptotic protein; programs; public health relevance; research clinical testing; response; small molecule; treatment strategy; tumor; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Most lung cancer cells are characterized by elevated levels of anti-apoptotic Bcl-2 family proteins and the resulting inhibition of cell-death influences tumorigenicity, metastatic behavior, chemoresistance and radioresistance. In non-small-cell lung cancer (NSCLC) upregulation of anti-apoptotic Bcl-2 proteins, such as Bcl-xL, Bcl-2 and Mcl-1, is often associated with resistance to traditional chemotherapy and radiation, which are therapeutic strategies that rely on the ability to induce apoptosis. Thus, novel optimized strategies for treatment of cancer might combine traditional chemotherapeutics with molecules that neutralize the effects of the anti-apoptotic Bcl-2 proteins. Already, Bcl-2- targeting antisense oligonucleotides (GenasenseTM) are in Phase III clinical trials for melanoma and chronic lymphocytic leukemia (CLL), a quintessential example of a human malignancy caused by defective programmed cell death and Bcl-xL/2 over- expression. Similarly, a dual Bcl-xL/Bcl-2 small molecule inhibitor (ABT-263, Abbott) is advancing clinical evaluation for patients affected by CLL. However, several studies suggest that in non-small cell lung cancers (NSCLC), in addition to Bcl-2 and Bcl-xL, Mcl-1 over-expression dictates resistance to chemotherapy and radiation. Hence, we propose to use a highly integrated multidisciplinary approach involving innovative structure-based design, medicinal chemistry, cell-based and in vivo studies to derive novel, potent and drug-like pan-Bcl-2 antagonists that primarily target Mcl-1, Bcl2 and Bcl-xL, focusing on their development against NSCLC. Given the arsenal of techniques and alternative approaches proposed, we anticipate that we will be able to identify novel pan-Bcl-2 antagonists that induce apoptosis in lung cancer cells that are resistant to current advanced compounds such as ABT-263 or Genasense.

描述(由申请人提供)：大多数肺癌细胞的特征是抗凋亡的Bcl-2家族蛋白水平升高，由此导致的细胞死亡抑制会影响肿瘤的致瘤性、转移行为、化疗耐药性和放射耐药性。在非小细胞肺癌(NSCLC)中，抗凋亡的Bcl2蛋白，如Bclxl、Bcl2和Mcl-1的上调往往与对传统化疗和放疗的耐药有关，而传统的化疗和放疗是依赖于诱导细胞凋亡的治疗策略。因此，治疗癌症的新的优化策略可能会将传统的化疗药物与中和抗细胞凋亡的Bcl-2蛋白的分子结合起来。目前，针对Bcl-2的反义寡核苷酸(GenasenseTM)已处于治疗黑色素瘤和慢性淋巴细胞白血病(CLL)的第三阶段临床试验，这是由程序性缺陷细胞死亡和Bcl-xL/2过度表达引起的人类恶性肿瘤的典型例子。同样，一种双重的Bclxl/Bcl2小分子抑制剂(ABT-263，Abbott)正在推进对CLL患者的临床评估。然而，一些研究表明，在非小细胞肺癌(NSCLC)中，除了Bcl2和Bclxl外，Mcl-1的过度表达还决定了对化疗和放射的抵抗。因此，我们建议使用高度集成的多学科方法，包括创新的基于结构的设计、药物化学、基于细胞的和体内研究，以获得新的、有效的和类似药物的、主要针对Mcl-1、Bcl2和Bclxl的PAN-Bcl-2拮抗剂，重点是它们对非小细胞肺癌的开发。考虑到所提出的各种技术和替代方法，我们预计我们将能够找到诱导肺癌细胞凋亡的新型PAN-Bcl2拮抗剂，这些药物对目前的先进化合物如ABT-263或Genasense具有耐药性。

项目成果

Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis.

• DOI: 10.1593/neo.13230
• 发表时间: 2013-05
• 期刊: Neoplasia
• 影响因子: 4.8
• 作者: S. Varadarajan;M. Butterworth;Jun Wei;M. Pellecchia;D. Dinsdale;G. Cohen

SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1.

• DOI: 10.1021/jm200826s
• 发表时间: 2011-09-08
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Rega, Michele F.;Wu, Bainan;Wei, Jun;Zhang, Ziming;Cellitti, Jason F.;Pellecchia, Maurizio
• 通讯作者: Pellecchia, Maurizio

An optically pure apogossypolone derivative as potent pan-active inhibitor of anti-apoptotic bcl-2 family proteins.

• DOI: 10.3389/fonc.2011.00028
• 发表时间: 2011
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Wei J;Stebbins JL;Kitada S;Dash R;Zhai D;Placzek WJ;Wu B;Rega MF;Zhang Z;Barile E;Yang L;Dahl R;Fisher PB;Reed JC;Pellecchia M
• 通讯作者: Pellecchia M