Perifosine treatment exhibits a complex molecular response including the inhibition of Akt or the induction of apoptosis via clustering of death receptors in lipid rafts. However, the molecular response can vary between different tumor entities and the contribution of each target pathway to the activity of Perifosine might be distinct depending on the tumor entity or the agent combined with Perifosine. In this review we discuss the current view on the mechanism of action of perifosine in cancer and the contribution of the molecular targets of Perifosine to its activity.

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As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC₅₀ values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.

Urea and aniline derivatives were active at low micromomolar IC50 values against a panel of seven cancer-related protein kinases.

A Convenient Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines Possessing Biological Activity. -Condensation of suitable diaminopyridines [cf. (III)] with α-ketoaldehyde derivatives results in a regioselective synthesis of pyrido[3,4-b]pyrazines (IV). The 8-bromo substituent is utilized for the introduction of a variety of N-substituents including, amino, anilines, amides, and ureas. -(ANTOINE, M.; GERLACH, M.; GUENTHER, E.; SCHUSTER, T.; CZECH, M.; SEIPELT, I.; MARCHAND*, P.; Synthesis 2012, 1, 69-82, http://dx.doi.org/10.1055/s-0031-1289613 ; Lab. Chim. Ther., Fac. Pharm., CNRS, Univ. Nantes, F-44035 Nantes, Fr.; Eng.) -Mais 17-180

The Ras/Raf/Mek/Erk and the PI3K/Akt signaling pathways are frequently deregulated in cancer due to activation of upstream receptors, decreased expression of tumor suppressors like PTEN or activating mutations of Ras, B-Raf or PI3K. Several clinical studies with kinase inhibitors targeting single members of the Ras/Raf/Mek/Erk or the PI3K/Akt pathway are ongoing. However, preclinical and clinical trials indicated limited success by single pathway inhibition and different resistance mechanisms were defined. Further clinical trials with drug combinations of Ras/Raf/Mek/Erk and PI3K/Akt suppressors have been initiated, suggesting a more favorable outcome than targeting only one single pathway, Ras/Raf/Mek/Erk or PI3K/Akt. We performed in-vitro combination experiments with Raf, Mek or Erk inhibitors and PI3K or Akt inhibitors in several human tumor cell lines. Strong synergy was achieved with various combinations including the Mek inhibitor CI-1040 and the PI3K inhibitor GDC-0941 (CI = 0.17) or the Erk inhibitor AEZS-131 and the PI3K inhibitor D-117073 (CI = 0.23) in A549 cells. Also Raf inhibitors like Sorafenib and Zelboraf were combined with different PI3K inhibitors, resulting in synergistic anti-proliferative activity. Due to the attractiveness of parallel inhibition of the Ras/Raf/Mek/Erk and PI3K/Akt pathways, we developed AEZS-136 that concurrently inhibits Erk1/2 (IC50 ∼ 50nM) and PI3K (IC50 ∼ 100nM) by an ATP competitive mode of action. Derivatives of the dual PI3K/Erk inhibitor were co-crystallized with Erk2 and PI3Kα enabling an optimization process by SAR driven medicinal chemistry. The anti-proliferative efficacy of AEZS-136 was evaluated in more than 40 human tumor cell lines and physico-chemical as well as in-vitro ADMET properties were widely assessed. Furthermore, the in-vivo pharmacokinetics and anti-tumor efficacy was explored. AEZS-136 was well tolerated and showed dose dependent inhibition of human colon tumor growth of up to 74% in a Hct116 mouse model. Here we present the concept of dual targeting of the Ras/Raf/Mek/Erk and the PI3K/Akt pathways, either by using drug combinations or our novel dual PI3K/Erk inhibitor. AEZS-136 is a small molecule in preclinical development showing a uniquely advantageous kinase inhibition profile. Broad clinical anti-tumor activity is expected for AEZS-136 in tumors with deregulated Ras/Raf/Mek/Erk and PI3K-Akt signaling. 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 871. doi:1538-7445.AM2012-871

The Ras/Raf/Mek/Erk and the PI3K-Akt signaling pathways are prime targets for drug discovery in proliferative diseases such as cancer. The results of research to date indicate that both the MAPK and the PI3K signaling pathways represent therapeutic intervention points for the clinical treatment of malignant tumors. Our multi-parameter optimization program for kinase inhibitor selectivity, cellular efficacy, physico-chemical and in-vitro ADMET properties has led to the identification of a small molecular compound class with an uniquely advantageous dual kinase inhibition profile. These ATP competitive compounds inhibit Erk and PI3K in the nanomolar range and exert high selectivity against other serine threonine and tyrosine kinases. The anti-tumor efficacy of these dual kinase inhibitors was evaluated in diverse human tumor cell lines like HCT116, A549, MDA-MB 468, PC-3 and others. Physicochemical and in-vitro ADMET and safety parameters have been widely assessed. Furthermore in-vivo pharmacokinetic experiments showed plasma profiles expected to result in beneficial in-vivo anti-tumor efficacy. Here we present the key characteristics of the compound class that led to the selection of AEZS-132 for in-vivo experiments with tumor bearing nude mice. The optimization of ADME and physicochemical properties such as solubility, permeability and metabolic stability by medicinal chemistry is ongoing. 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 4474.

S y n t h e s i s o f N o v e l 2 , 8 -D i s u b s t i t u t e d P y r i d o [ 3 , 4 -b ] p y r a z i n e sAbstract: A regioselective synthetic route to 2,8-disubstituted pyrido [3,4-b]pyrazines, by initial condensation reaction between suitable diaminopyridines and a-keto aldehydes equivalents, has been developed. Focusing on the functionalization on C-8, 2-aryl-8-bromo-and 8-amino-2-arylpyrido[3,4-b]pyrazines have been synthesized. Anilines, amides, and ureas have been introduced at the 8-position from key intermediates. 2,8-Disubstituted pyrido [3,4-b]pyrazines thus prepared were found to be of biological interest.In recent years, some pyrido[2,3-b]pyrazines and pyrido[3,4-b]pyrazines have been described in the literature as compounds with promising biological properties. In particular, 2,3,8-trisubstituted pyrido[2,3-b]pyrazines have been used for the treatment of malignant tumors and other diseases associated to pathological cell proliferations. 1 Other compounds bearing a pyridopyrazine scaffold have been described as vasculostatic agents (by inhibition of Src-family kinases: c-Src and Yes) and as inhibitors of FtsZ polymerization. 2 In addition, pyrido[3,4-b]pyrazine derivatives exhibited tubulin polymerization inhibition in the micromolar range. 3As part of our continuing efforts to identify new chemical classes of kinase inhibitors, we previously developed an efficient synthetic approach for the preparation of 2,3,8-trisubstituted pyrido[3,4-b]pyrazines, 4 but unfortunately they did not exhibit any kinase inhibitory activity (data not shown).A literature survey revealed that no example of 2,8-disubstituted pyrido[3,4-b]pyrazines targeting kinase pathway was described. To our knowledge, only a few papers have reported on the preparation of 2-or 2,8-disubstituted pyrido[3,4-b]pyrazines. 5-9 Thus, it was decided to synthesize new compounds with a pyrido[3,4-b]pyrazine scaffold bearing only one aryl group, in position 2, and an urea, an amide or an aniline in position 8, expecting to better interact with the target protein.In this paper, we present a regioselective synthetic route to 2,8-disubstituted pyrido[3,4-b]pyrazines obtained by initial condensation reaction between suitable diaminopyridines and a-keto aldehyde equivalents (Scheme 1). Scheme 1 Structures of synthesized 2,8-disubstituted pyrido[3,4-b]pyrazinesOur synthetic strategy was to functionalize directly 2-and 8-positions of the pyrido[3,4-b]pyrazine scaffold by ringclosing reaction. We envisioned to prepare our key intermediates, 2-aryl-8-bromo-and then 8-amino-2-arylpyrido [3,4-b]pyrazines by an initial condensation reaction between 3,4-diamino-5-bromopyridine and an a-dioxo partner.b-Oxosulfoxides or corresponding hemithioacetals were first used as 1,2-diketone equivalents. 6,10 The reaction was carried out in the past with 3,4-diaminopyridine and 2-aryl-2-oxoethyl methyl sulfoxides in a mixture of benzene and acetic acid to give selectively 2-arylpyrido [3,4-b]pyrazines. 6 This synthetic approach was applied to prepare 2-aryl-8-bromopyrido [...