Jeffrey Forrester

Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer

By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compound that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.

Overview of the Alliance for Cellular Signaling

The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells — B lymphocytes (the cells of the immune system) and cardiac myocytes — to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells — B lymphocytes (the cells of the immune system) and cardiac myocytes — to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.

CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity

Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. (c)2010 AACR.

CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy.

Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types. Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models. Results: CUDC-305 shows high affinity for HSP90α/β (IC50, ∼100 nmol/L) and HSP90 complex derived from cancer cells (IC50, 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC50, 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non–small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models. Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.

Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non–small cell lung cancer

CUDC-305 is a heat shock protein 90 (HSP90) inhibitor of the novel imidazopyridine class. Here, we report its activities in non–small cell lung cancer (NSCLC) cell lines with gene deregulations conferring primary or secondary resistance to epidermal growth factor receptor (EGFR) inhibitors. We show that CUDC-305 binds strongly to HSP90 extracted from erlotinib-resistant NSCLC cells (IC50 70 nmol/L). This result correlates well with the potent antiproliferative activity in erlotinib-resistant NSCLC cell lines (IC50 120–700 nmol/L) reported previously. Furthermore, it exhibits durable inhibition of multiple oncoproteins and induction of apoptosis in erlotinib-resistant NSCLC cells. CUDC-305 potently inhibits tumor growth in subcutaneous xenograft models of H1975 and A549, which harbor EGFR T790M mutation or K-ras mutations conferring acquired and primary erlotinib resistance, respectively. In addition, CUDC-305 significantly prolongs animal survival in orthotopic lung tumor models of H1975 and A549, which may be partially attributed to its preferential exposure in lung tissue. Furthermore, CUDC-305 is able to extend animal survival in a brain metastatic model of H1975, further confirming its ability to cross the blood-brain barrier. Correlating with its effects in various tumor models, CUDC-305 induces degradation of receptor tyrosine kinases and downstream signaling molecules of the PI3K/AKT and RAF/MEK/ERK pathways simultaneously, with concurrent induction of apoptosis in vivo. In a combination study, CUDC-305 enhanced the antitumor activity of a standard-of-care agent in the H1975 tumor model. These results suggest that CUDC-305 holds promise for the treatment of NSCLC with primary or acquired resistance to EGFR inhibitor therapy. [Mol Cancer Ther 2009;8(12):3296–306]

Abstract 3249: Design and synthesis of imidazopyridine derivatives as novel HSP90 inhibitors for the treatment of cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The molecular chaperone heat shock protein 90 (HSP90) is involved in folding and stabilization of a wide range of client proteins, including key proteins involved in cancer. Through structure-based design, we synthesized a novel imidazopyridine class of potent HSP90 inhibitors. The synthesis and SAR surrounding this class of compounds will be discussed. The extensive SAR study and lead optimization resulted in the identification of the development candidate CUDC-305, later renamed Debio 0932. Debio 0932 displays high oral bioavailability (96% in mouse), high drug concentrations and a prolonged half-life (20 hr) in tumor tissues. In vitro, Debio 0932 displays potent HSP90 inhibitory activity (IC50, 100 nM) as well as anti-proliferation and apoptosis-inducing activities against a broad range of cancer cell lines (IC50, 40 – 900 nM). In vivo, Debio 0932 is highly effective against various cancer models including NSCLC, AML, breast and colorectal cancers, as well as brain cancers, benefited by its ability to cross the blood-brain barrier to reach therapeutic levels in brain tissue. Debio 0932 also exhibits high selectivity and a favorable safety profile. It was therefore selected as a drug candidate and is currently in Phase 1 clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3249. doi:10.1158/1538-7445.AM2011-3249

Abstract 2619: Potential advantages of CUDC-101, a multi-targeted HDAC, EGFR and HER2 inhibitor, on preventing drug resistance and tumor metastasis

CUDC-101 is a novel small-molecule multi-target anti-cancer agent currently in Phase Ib clinical trial, which targets histone deacetylase (HDAC), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor2 (HER2). Previously, we reported that CUDC-101 has potent anti-proliferative and pro-apoptotic activities in cultured tumor cells and in vitro xenograft models when compared to other single-target agents. Additionally, we demonstrated that CUDC-101 reduces the levels of phosphorylated and total MET. MET amplification and secondary EGFR mutation are two validated mechanisms responsible for EGFR tyrosine kinase inhibitor (TKI) drug resistance in patients. In an effort to expand on our previous findings, we further substantiate here that cancer cells harboring MET amplification are sensitive to CUDC-101. This result, together with the finding that cancer cells containing the EGFR-T790M mutation are sensitive to CUDC-101, suggests that RTK inhibitor-resistant tumor cells are sensitive to treatment with CUDC-101. Additionally, erlotinib-resistant HCC827 cells, which lost their EGFR dependence, are still sensitive to treatment with CUDC-101. Interestingly, this drug-resistant cell line shows neither secondary EGFR mutation nor c-Met amplification, suggesting that CUDC-101 has the potential to overcome drug resistance through other mechanisms. Because c-Met plays an important role in metastasis, we further investigated the effect of CUDC-101 in regulating cell motility, and demonstrate that CUDC-101 can induce E-cadherin accumulation in MDA-MB-231 cells and inhibit EGF induced epithelial-mesenchymal transition (EMT) in in vitro cultured cell and in vivo animal models. In vitro functional study also shows that CUDC-101 reduces tumor cell migration and invasion. Together, our findings suggest that CUDC-101, an investigational anti-cancer drug, may provide great potential for simultaneously overcoming tumor growth, metastasis, and drug resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2619. doi:10.1158/1538-7445.AM2011-2619

Abstract 4469: Antitumor activity of a single small molecule agent targeting Pi3K/mTor and HDAC

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Activation of the PI3K-Akt-mTOR signaling pathway plays a crucial role in cancer development and progression. Inhibition of this pathway has been investigated extensively as cancer therapy recently. However, primary or acquired resistance may present a major challenge to the success of inhibitors targeting this pathway due to the existence of redundant and compensatory pathways in cancer cells. In an effort to enhance anti-tumor activity and overcome these limitations, we have developed small-molecule compounds that are able to simultaneously inhibit both PI3K/mTOR and HDAC based on the rationale of synergistic effects of inhibition of these molecule targets in cancer cells. The lead compound exhibits potent inhibition of Pi3K subtypes and mTOR as well as HDAC. In cell proliferation assays, this compound displays potent anti-proliferation activity in cell lines from a variety of tumor types, including those cell lines with genetic mutations responsible for resistance to Pi3K inhibitors. In contrast to single-target PI3K inhibitors or PI3K/mTor dual inhibitors, this compound is able to simultaneously suppress both the Pi3K-Akt-mTOR and the MAPK signaling pathway due to epigenetic modifications via HDAC inhibition. This compound has a half-life of more than 10 hours in murine tumors, induces apoptosis and inhibits cell proliferation up to 48 hours following a single dose of the compound to tumor bearing animals. Efficacy studies in various tumor xenografts indicate that this compound has more potent antitumor activity than a leading Pi3K inhibitor and a dual Pi3K/mTor inhibitor, both of which are in clinical development, at doses causing no obvious side-effects to the tumor-bearing animals. This compound is under preclinical toxicology evaluation to support for further development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4469.