Targeted therapy has changed cancer treatment, but blocking a single pathway is often ineffective against aggressive solid tumors, due to feedback and activation of alternative pathways. The unique prolyl isomerase Pin1 is abnormally activated in most human tumors and promotes cancer and cancer stem cells by turning on and off at least 42 oncogenes and 21 tumor suppressors, respectively, including many non- druggable transcription factors. Thus, Pin1 is an exciting potential cancer target for simultaneously blocking numerous cancer-driving pathways. However, currently available Pin1 inhibitors lack the specificity and cellular potency required to explore the therapeutic potential of Pin1 as an anti-cancer target. Using the high-affinity Pin1 catalytic peptidomimetic inhibitor pTide as a starting point, we designed and synthesized the first potent covalent Pin1 inhibitors. We have developed efficient biochemical and cellular screening cascade that will guide Pin1 inhibitor optimization. Using these screens, we have identified a number of lead Pin1 inhibitors, including all-trans retinoic acid (ATRA), an approved therapy for acute promyelocytic leukemia (APL), but whose drug target still remains elusive. We discovered that ATRA binds to, inhibits and ultimately induces degradation of active Pin1 selectively in cancer cells. Such ATRA- induced Pin1 ablation exerts potent anticancer activity against APL by degrading PML-RAR? that drives leukemia stem cells, and against triple negative breast cancer (TNBC) by reducing stability of a number of oncogenes and also increasing protein stability of several tumor suppressors. These results provide a rationale for developing more potent and specific Pin1 inhibitors to target a common oncogenic mechanism. In this proposal, we have assembled a multi-disciplinary team that includes Pin1 cancer biology, Pin1 drug screen and inhibitor validation (KP Lu and XZ Zhou, BIDMC), medicinal chemistry (N Gray, DFCI), structural biology (S Dhe-Paganon, DFCI), computational chemistry (N London, Weizmann), and breast cancer translational research (G Wulf, BIDMC). We have discovered an unprecedented means of developing selective Pin1 inhibitors by covalently targeting the critical active site cysteine (Cys113). We have obtained compelling published and preliminary data of the activity of Pin1 inhibitors in a large number of cancers, but here we propose to focus on investigating the potential of targeting Pin1 for the treatment of TNBC, which has the worst prognosis, with no targeted therapy available and where Pin1 plays a critical pathophysiological role. This will be accomplished through a focused medicinal chemistry campaign (Aim 1.1) and guided by detailed mechanistic characterization (Aim 1.2) and co-crystal structural determination (Aim 2), followed by preclinical evaluation in tumor cell and patient-derived xenograft models of TNBC (Aim 3). Our goal is to develop optimized Pin1 inhibitors with properties suitable to interrogate the pharmacological consequences of inhibiting Pin1 enzymatic activity in cellular and in vivo models of TNBC.

Public Health Relevance

Breast cancer is the most commonly diagnosed cancer in women in the US and also around the world, with triple negative breast cancer having the worst prognosis. We have identified a potential enzyme drug target called Pin1 that functions as a ?master? regulator of multiple cancer-driving pathways and found a series of drug leads to inhibit Pin1. This grant will optimize prototype drugs directed against Pin1 and evaluate whether they are effective in treating triple negative breast cancer in preclinical breast cancer models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA205153-02
Application #
9407303
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Alley, Michael C
Project Start
2017-01-03
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215