The Development of Novel Inhibitors of BCL2 Gene Expression as Anticancer Therape

Project: Research project

Description

Project Summary
Evasion of apoptosis is a hallmark of cancer and is associated with oncogenesis, tumor maintenance, and
resistance to conventional chemotherapy. BCL-2 was the first identified anti-apoptotic factor and is a member
of the BCL-2 family of proteins that cooperate in the regulation of programmed cell death. BCL-2 plays a
dominant role in the survival of multiple lymphoid malignancies and has consequently become an active target
for drug discovery programs seeking to reactivate dormant apoptotic signaling in cancer cells or enhance the
activity of cytotoxic anticancer drugs. The only small-molecule-based approach has been to target the BH3
binding domain of Bcl-2, thereby blocking interaction with other pro-apoptotic Bcl-2 family members. However,
the recent suspension of the BH3 mimetic ABT-119 from clinical trials, due to the occurrence of tumor lysis
syndrome, has cast some doubt over the potential safety of the BH3 mimetic approach and increased the need
for alternative strategies to target BCL-2.
In common with many other genes that cooperate in the development and maintenance of cancer, BCL-2
contains a highly plastic, GC-rich transcriptional regulatory element in its promoter region. Pioneering work at
the University of Arizona has shown that this regulatory element is capable of forming DNA secondary
structures called G-quadruplex DNA (G-rich strand) and i-motif DNA (C-rich strand) and that these DNA
secondary structures regulate transcription. A high-throughput screening assay designed to identify small
molecules capable of stabilizing/destabilizing the BCL-2 i-motif sequence produced a small molecule from the
steroidal chemotype (IMC-76). Subsequent studies have demonstrated that IMC-76 decreases BCL-2
expression in cell culture and in mouse xenograft tumor cells. Importantly, IMC-76 significantly potentiates
apoptosis induced by conventional chemotherapy drugs in cell culture and demonstrates considerable synergy
when combined with chemotherapy drugs in mouse cancer xenograft models.
The ultimate goal of this proposal is to advance suitably optimized analogs of IMC-76 into IND-enabling studies
and eventual phase 1 clinical trials. We propose a limited round of synthetic chemistry for the purpose of
optimizing potency for lowering BCL-2 expression in cells and synergy with cytotoxic anticancer drugs in cell
culture. Furthermore, this optimization strategy will allow us to explore potential off-target effects associated
with the steroidal chemotype by screening analogs in biochemical nuclear receptor assays. Qualified lead
molecules will be subjected to pharmacokinetic analysis in rats, both chronic and acute tolerability studies in
mice, and efficacy studies in combination with standard-of-care chemotherapy drugs in lymphoma mouse
xenograft models. Collectively these studies will enable us to select an optimized lead candidate for
advancement into formal preclinical studies.
StatusFinished
Effective start/end date9/20/142/29/16

Funding

  • National Institutes of Health: $224,998.00

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Gene Expression
Neoplasms
G-Quadruplexes
Drug Therapy
Pharmaceutical Preparations
Heterografts
Cell Culture Techniques
Transcriptional Regulatory Elements
Maintenance
High-Throughput Screening Assays
Clinical Trials, Phase I
Nucleotide Motifs
Drug Discovery
Standard of Care
Cytoplasmic and Nuclear Receptors
Genetic Promoter Regions
Plastics
Lymphoma
Suspensions
Carcinogenesis

ASJC

  • Medicine(all)