Marielle Fournel

Discovery of N-(2-Aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an Orally Active Histone Deacetylase Inhibitor

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.

Design and synthesis of a novel class of histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities.

Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors

In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.

Sulfamides as novel histone deacetylase inhibitors

The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long-chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors.

Synthesis and evaluation of lysine derived sulfamides as histone deacetylase inhibitors

We have recently reported on a novel class of histone deacetylase (HDAC) inhibitors bearing a sulfamide group as the zinc-binding unit. Herein, we report on the synthesis of sulfamide based inhibitors designed around a lysine scaffold and their structure-activity relationships against HDAC1 and HDAC6 isotypes as well as 293T cells. Our efforts led us to an improvement of the originally disclosed lysine-based sulfamide, 2a to compound 12h which has equal potency in enzyme and cell-based assays as well as enhanced metabolic stability and PK profile.

4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors.

The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.

Abstract 1790: The combination of MGCD265, a Met/VEGFR inhibitor in clinical development, and erlotinib potently inhibits tumor growth by altering multiple pathways including glycolysis

MGCD265 is an oral, multitargeted, receptor tyrosine kinase inhibitor in clinical development. MGCD265 targets the Met, VEGFR1, 2, 3, Tie2 and Ron receptor tyrosine kinases and blocks key pathways regulating cancer development and progression. Met-targeted agents, including MGCD265, have shown early signs of clinical activities when combined with EGFR inhibitors. While this combination is supported by a large body of evidence indicating that Met and EGFR functionally cooperate to amplify activating signals, how the combination of agents targeting these two pathways leads to efficient anti-tumor responses remains to be elucidated. We have previously demonstrated that the combination of MGCD265 with erlotinib achieved greater tumor growth inhibition than treatment with either agent alone in multiple xenografts including a gastric cancer model in which Met is amplified (MKN45). We performed gene expression analyses in this model to gain insight into the molecular mechanisms underlying the efficient anti-tumor activities of MGCD265 in combination with erlotinib. While these studies revealed the inhibition of cell growth and the induction of apoptosis pathways as enhanced by this combination, the regulation of glycolysis surfaced as a novel pathway altered by this combination. Although genes regulating this pathway were partly downmodulated by either agent alone, the combination significantly enhanced this effect. A key mediator of glycolysis, hexokinase 2 (HK2), known to be elevated in cancer cells and essential for the switch to aerobic glycolysis as well as for mitochondrial-initiated cell death, was significantly downregulated by the combination. Furthermore, PFKFB3, PGK, ENO1, PKM2 were also inhibited by the combination. These results suggest that regulating tumor cell glycolysis may present a novel pathway through which MGCD265 could block tumor cell growth. Thus, the inhibition of multiple molecular pathways involved in cancer growth and progression provides a rationale for the clinical development of MGCD265 in combination with erlotinib. Early results from an ongoing Phase I/II clinical trial of MGCD265 in combination with erlotinib has demonstrated encouraging signs of activity in gastric cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1790. doi:1538-7445.AM2012-1790

SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.

Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors

A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.

Abstract 930: Preclinical characterization of MG516, a novel inhibitor of receptor tyrosine kinases involved in resistance to targeted therapies.

Despite breakthroughs in the clinical development of tyrosine kinase inhibitors, challenges remain in overcoming resistance to these molecular targeted therapies. Advances in our understanding of mechanisms of resistance to targeted agents will improve patient outcome. While secondary mutations play a key role, the activation of parallel signaling pathways has been shown to alter the sensitivity to targeted inhibition. Resistance to inhibitors of the EGFR or VEGFR families may occur through the activation of Met, EphA2 and Axl receptor tyrosine kinase pathways, suggesting combined inhibition of these targets as a strategy to prevent resistance to approved EGFR- and VEGFRs -targeted therapies. We have developed a novel multitargeted receptor tyrosine kinase inhibitor, MG516, with nanomolar activities in in vitro enzymatic assays against members of the Eph receptor family, Axl, Met and VEGFR1,2,3. In carcinoma cell lines, MG516 potently inhibits phosphorylation of EphA2, Axl and Met. Inhibition of Met downstream signaling as well as the inhibition of Met-dependent biological endpoints, such as motility and wound healing is also achieved. In human umbilical vein endothelial cells (HUVECs),VEGFR2 activation and VEGF-dependent angiogenesis are blocked. Potent anti-tumor activity is demonstrated across a broad range of human xenograft models including lung, gastric, glioblastoma, colorectal and breast carcinomas. Anti-tumor activity is achieved at oral doses as low as 2.5mg/kg in the absence of overt toxicity, weight loss or myelosuppression. Immunohistochemistry analyses of xenograft tumors after treatment with MG516 reveal a decrease in the proliferation of tumor cells, a decrease in tumor vascularization, pharmacodynamic inhibition of target phosphorylation and decreases in target expression, including EphA2. Consistent with targeting multiple oncogenic pathways simultaneously, the combination of MG516 with EGFR inhibition results in improved tumor growth inhibition. Importantly, in a gastric cancer model exhibiting resistance to sunitinib following prolonged treatment with this agent, MG516 induces tumor regression. Thus, MG516 offers potential for clinical development of a novel therapeutic, by targeting a combination of oncogenic kinases involved in tumor development, progression and resistance to targeted therapies. Citation Format: Normand Beaulieu, Helene Sainte-Croix, Claire Bonfils, Michael Mannion, Stephane Raeppel, Lubo Isakovic, Stephen Claridge, Oscar Saavedra, Franck Raeppel, Arkadii Vaisburg, James Wang, Marielle Fournel, Jeffrey M. Besterman, Christiane R. Maroun. Preclinical characterization of MG516, a novel inhibitor of receptor tyrosine kinases involved in resistance to targeted therapies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 930. doi:10.1158/1538-7445.AM2013-930