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Project 3: Mcl-1 inhibitors for the treatment of breast cancer

Specific Aims

During breast tumorigenesis, deregulation of apoptotic signaling promotes tumor cell survival and limits cell death processes required to maintain normal tissue metabolism and function. Defects in apoptotic signaling are central to tumor initiation and maintenance of breast cancer cells, particularly in the context of unregulated tumor cell proliferation. Therefore, neutralizing the function of anti-apoptotic proteins may offer an effective strategy to arrest or eliminate breast cancer cells.

Amplification of the gene encoding the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) is a common genetic aberration in human cancer. Mcl-1 overexpression in human breast cancer has been associated with high tumor grade and poor patient survival. Preclinical evidence suggests that Mcl-1 is a promising target for the treatment of breast cancers including the highly aggressive triple negative breast cancer (TNBC) subtype, which lacks molecularly targeted therapies. Further, Mcl-1 activity has been implicated in resistance to multiple therapies used in patients with breast cancer including microtubule-targeting agents. Therefore, we propose that targeted inhibition of Mcl-1 will result in restoration of apoptotic signaling and increased sensitivity to chemotherapy in Mcl-1-dependent breast tumors.

Mcl-1 mediates its effects primarily through protein-protein interactions and is therefore considered difficult to target with small molecules. Although attempts to target Mcl-1 have been reported, compounds specifically targeting Mcl-1 have not entered the clinic. Using a combination of fragment-based methods and structure-based design, we have discovered novel small molecules that bind to Mcl-1 with high affinity (KD = 35nM) for the BH3-binding pocket, the motif used by Mcl-1 to bind to and sequester pro-apoptotic proteins. A similar strategy led to the successful development of ABT-263 (Navitoclax), a Bcl-2/Bcl-xL inhibitor currently in clinical trials (discovery led by Stephen Fesik, PhD, co-Leader of this Project). We propose to further refine the current lead compounds to generate potent Mcl-1 inhibitors with sub-nanomolar binding affinities, robust cellular efficacies and desirable drug metabolism and pharmacokinetics (DMPK) profiles. We will use these compounds to evaluate a therapeutic strategy in breast cancer models. Our goal is to discover a small molecule Mcl-1 inhibitor that will be suitable for early clinical trials focused in patients with the triple negative subtype of breast cancer upon completion of the proposed Aims.

Aim 1: Discover potent (sub-nanomolar) and specific Mcl-1 inhibitors using fragment-based methods and structure-based design. Compounds binding tightly to Mcl-1 will be optimized using structure-based design and an iterative medicinal chemistry approach. Binding to Mcl-1 will be analyzed and the results will be incorporated into future analog design.

Aim 2: Optimize potent Mcl-1 inhibitors for their cell-based activities, pharmaceutical properties and in vivo efficacy in breast cancer models. A panel of TNBC cell lines will be analyzed using RNAi methodology to assess relative sensitivity to Mcl-1 loss of function. Sensitive cells will be used to test our lead Mcl-1 compounds in culture and in xenograft in vivo. In a genetically engineered mouse model of TNBC that develops mammary tumors overexpressing human Mcl-1, we will determine the antitumor effect of the lead Mcl-1 compounds in the context of an intact immune system and tumor microenvironment.

Aim 3: Identify genetic and molecular biomarkers of sensitivity to Mcl-1 inhibition, alone or in combination with other anticancer agents. The lead Mcl-1 inhibitory compounds will be tested in combination with chemotherapeutic drugs, including microtubule inhibitors and other Bcl-2 family inhibitors that have a different binding profile (ABT-263, ABT-199). Gene expression profiles and genomic aberrations in Mcl-1 inhibitor sensitive vs. resistant TNBC cell lines will be analyzed to identify molecular markers that predict response to the inhibitors as single agents and in combination with taxanes, Bcl-2 family inhibitors and other chemotherapeutic agents. As part of these analyses, we will determine the relevance of Mcl-1 gene copynumber and/or protein overexpression to sensitivity to Mcl-1 inhibitors.