The objectives of this U19 proposal are to design and synthesize highly potent and specific small-molecule inhibitors of Bcl-2/Bcl-xL. We will test these inhibitors in vitro and in vivo to determine their therapeutic potential in prostate cancer animal models. Our central rationale/ hypothesis is that (1) hormone-refractory prostate cancer cells with high levels of Bcl-2/Bcl-xL proteins depend upon the protection of Bcl-2/xL for survival advantage and so become resistant to chemotherapeutic agents; (2) inhibition of the anti-apoptotic function of Bcl-2/xL using a potent, cell-permeable small-molecule inhibitor may overcome chemoresistance and improve the efficacy of current chemotherapy, representing a highly effective and novel strategy for the treatment of hormone-refractory prostate cancer by overcoming apoptosis-resistance. To test our hypothesis, we propose to carry out three interrelated Specific Aims:
Aim 1 : To evaluate the in vitro anti-tumor activity of the most potent and promising Bcl-2 small-molecule inhibitors and investigate their mechanism of action in apoptosis induction;
Aim 2 : To evaluate the in vivo anti-tumor activity of the most potent and promising Bcl-2/xL inhibitors;
Aim 3 : To evaluate the Bcl-2 family of proteins in a VCaP model during tumor progression/transition from androgen sensitive to insensitive prostate cancer and the therapeutic potential of Bcl-2/xL inhibitors in overcoming chemoresistance of the androgen independent VCaP. Successfully carried out, our in vitro and in vivo studies will provide the important proof-of-concept that a highly potent and specific small-molecule inhibitor of Bcl-2/xL may have a great therapeutic potential to be developed as a new and effective therapy for treating hormone-refractory prostate cancer, alone and in combination with chemotherapy by overcoming apoptosis-resistance. This will provide the critical impetus to bring the best Bcl-2/xL small-molecule inhibitor to advanced preclinical development and future clinical studies as an entirely new class of cancer therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZCA1-SRRB-U (J1))
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University of Michigan Ann Arbor
Ann Arbor
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Bai, Longchuan; Chen, Jianfang; McEachern, Donna et al. (2014) BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo. PLoS One 9:e99404
Aguilar, Angelo; Zhou, Haibin; Chen, Jianfang et al. (2013) A potent and highly efficacious Bcl-2/Bcl-xL inhibitor. J Med Chem 56:3048-3067
Chen, Jianfang; Zhou, Haibin; Aguilar, Angelo et al. (2012) Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression. J Med Chem 55:8502-14
Zhou, Haibin; Aguilar, Angelo; Chen, Jianfang et al. (2012) Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity. J Med Chem 55:6149-61
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Zhou, Haibin; Chen, Jianfang; Meagher, Jennifer L et al. (2012) Correction to Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold. J Med Chem 55:5987
Zhou, Haibin; Chen, Jianfang; Meagher, Jennifer L et al. (2012) Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold. J Med Chem 55:4664-82
Azmi, Asfar S; Aboukameel, Amro; Banerjee, Sanjeev et al. (2010) MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function. Eur J Cancer 46:1122-31
Azmi, Asfar S; Philip, Philip A; Aboukameel, A et al. (2010) Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy. Curr Cancer Drug Targets 10:319-31
McGregor, Natalie; Patel, Lalit; Craig, Matthew et al. (2010) AT-101 (R-(-)-gossypol acetic acid) enhances the effectiveness of androgen deprivation therapy in the VCaP prostate cancer model. J Cell Biochem 110:1187-94

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