Andreas Sellmer

Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: a series of imatinib hybrides as potent inhibitors of wild-type and mutant BCR-ABL, PDGF-Rbeta, and histone deacetylases.

Inhibitors of histone deacetylases are a new class of cancer therapeutics with possibly broad applicability. Combinations of HDAC inhibitors with the kinase inhibitor 1 (Imatinib) in recent studies showed additive and synergistic effects. Here we present a new concept by combining inhibition of protein kinases and HDACs, two independent pharmacological activities, in one synthetic small molecule. In general, the HDAC inhibition profile, the potencies, and the probable binding modes to HDAC1 and HDAC6 were similar as for 6 (SAHA). Inhibition of Abl kinase in biochemical assays was maintained for most compounds, but in general the kinase selectivity profile differed from that of 1 with nearly equipotent inhibition of the wild-type and the Imatinib resistant Abl T(315)I mutant. A potent cellular inhibition of PDGFR and cytotoxicity toward EOL-1 cells, a model for idiopathic hypereosinophilic syndrome (HES), are restored or enhanced for selected analogues (12b, 14b, and 18b). Cytotoxicity was evaluated by using a broad panel of tumor cell lines, with selected analogues displaying mean IC(50) values between 3.6 and 7.1 muM.

Novel chimeric histone deacetylase inhibitors: a series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity.

Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.

Drugging the HDAC6–HSP90 interplay in malignant cells

Acetylation and deacetylation cycles regulate crucial biological processes. The enzymes deacetylating lysine residues are termed histone deacetylases (HDACs). Eighteen deacetylases have been isolated from mammalian cells. There is an intense search underway for individual functions of these enzymes and for selective histone deacetylase inhibitors (HDACi). HDAC6 in particular has unique cytoprotective functions that rely on its ability to ensure protein homeostasis and to prevent protein aggregation. The chaperone heat shock protein 90 (HSP90) also safeguards proteins and is deacetylated by HDAC6. Current data illustrate the complexity and importance of the HDAC6-HSP90 interplay. In this review, we discuss how recently identified HSP90-dependent regulators of posttranslational modifications (PTMs) of HDAC6 dictate its functions, and how HDACi-induced acetylation of HSP90 might control oncologically relevant proteins, especially in leukemic cells. Additionally, we discuss small molecules blocking HDAC6 and how such agents could become therapeutically relevant. We summarize structure-function relationships that determine the specificity of drugs against HDAC6.

2-Arylamino-4-Amino-5-Aroylthiazoles. "One-Pot" Synthesis and Biological Evaluation of a New Class of Inhibitors of Tubulin Polymerization

The essential role of microtubules in mitosis makes them a major target of compounds useful for cancer therapy. In our search for potent antitumor agents, a novel series of 2-anilino-4-amino-5-aroylthiazoles was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. SAR was elucidated with various substitutions on the phenylamino and aroyl moiety at the 2- and 5-positions, respectively, of the 4-aminothiazole skeleton. Tumor cell exposure to several of these compounds led to the arrest of HeLa cells in the G2/M phase of the cell cycle and induction of apoptosis.

Novel inhibitors of epidermal growth factor receptor: (4-(Arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones.

Several members of the quinazoline class of known tyrosine kinase inhibitors are approved anticancer agents, often showing selectivity for receptors of the HER/ErbB-family. Combining structural elements of this class with the bisindolylmethanone-structure led to a series of novel compounds. These compounds inhibited EGFR in the nanomolar range. Moreover, inhibition of EGFR autophosphorylation in intact A431 cells was shown, with IC(50) values ranging form 0.3-1μM for compound 42, and 0.1-0.3μM for 45. In a panel of 42 human tumor cell lines the sensitivity profile of the novel compounds was shown to be similar to that of the quinazoline class of tyrosine kinase inhibitors lapatinib and erlotinib (Tarceva®).

Class I histone deacetylases regulate p53/NF-κB crosstalk in cancer cells

The transcription factors NF-κB and p53 as well as their crosstalk determine the fate of tumor cells upon therapeutic interventions. Replicative stress and cytokines promote signaling cascades that lead to the co-regulation of p53 and NF-κB. Consequently, nuclear p53/NF-κB signaling complexes activate NF-κB-dependent survival genes. The 18 histone deacetylases (HDACs) are epigenetic modulators that fall into four classes (I-IV). Inhibitors of histone deacetylases (HDACi) become increasingly appreciated as anti-cancer agents. Based on their effects on p53 and NF-κB, we addressed whether clinically relevant HDACi affect the NF-κB/p53 crosstalk. The chemotherapeutics hydroxyurea, etoposide, and fludarabine halt cell cycle progression, induce DNA damage, and lead to DNA fragmentation. These agents co-induce p53 and NF-κB-dependent gene expression in cell lines from breast and colon cancer and in primary chronic lymphatic leukemia (CLL) cells. Using specific HDACi, we find that the class I subgroup of HDACs, but not the class IIb deacetylase HDAC6, are required for the hydroxyurea-induced crosstalk between p53 and NF-κB. HDACi decrease the basal and stress-induced expression of p53 and block NF-κB-regulated gene expression. We further show that class I HDACi induce senescence in pancreatic cancer cells with mutant p53.

Chimerically designed HDAC- and tyrosine kinase inhibitors. A series of erlotinib hybrids as dual-selective inhibitors of EGFR, HER2 and histone deacetylases

The regulation of chromatin structure and, therefore, transcriptional activity of histone proteins by reversible lysine acetylation is an important posttranslational modification. Inhibitors of histone deacetylase (HDAC) are considered as promising new anti-neoplastic drugs. The hydroxamic acid SAHA e.g. is currently used in the treatment of advanced primary cutaneous T-cell lymphoma. The EGFR protein tyrosine kinase inhibitor erlotinib is a prominent drug in cancer chemotherapy and currently approved for treatment of non-small cell lung cancer. In this report, we present a novel strategy for cancer drug development by a combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining two distinct pharmacological properties in one molecule, we expect a broader activity spectrum and less likelihood of drug resistance in cancer patients. The combination led to substances with both HDAC inhibitory properties and EGFR as well as HER2 kinase inhibitory activities.

Development of Tubulin Inhibitors as Antimitotic Agents for Cancer Therapy

ABSTRACT: Cancer represents one of the most threatening diseases of mankind. Within the last decade, our understanding of malignant cell growth and regulation of the cell cycle machinery has offered several new molecular targets with the promise of higher selectivity in human cancer therapy. Within mitosis, αβ-tubulin heterodimers, building up the mitotic spindle, are still an attractive target in the development of anticancer drugs. In the following article, we review the recent advances in the development of tubulin interfering agents. These agents are divided according to their mode of action into colchicine site binder, vinca -alkaloid related drugs and those interacting with the Taxol binding site and functioning as stabilising agents. Since clinically used compounds such as Paclitaxel or Vincristine are facing severe disadvantages, namely a small therapeutic window, restrictions in bioavailability and solubility, a complex synthesis and most importantly development of drug resistance in patients, special emphasis is laid on the development of synthetic small molecule tubulin inhibitors (SMTIs). These new agents offer promise for the rational design of new chemotherapeutic drugs by their simple structures and potential broad applicability in 2 nd and 3 rd line standard chemotherapy regimens towards resistant tumours. In this regard, most SMTIs are not P-glycoprotein substrates. Most tumours can only grow beyond a critical size by inducing the formation of new blood vessels, a process called neovascularisation. SMTIs as well as natural tubulin inhibitors have been described to interfere with this angiogenic process and some, like combretastatin A4 phosphate, are even described as selectively damaging tumour vasculatures. Finally, the present review emphasises the preclinical and clinical status of tubulin inhibitors in cancer therapy.

Marbostat 100 defines a new class of potent and selective antiinflammatory and antirheumatic histone deacetylase 6 inhibitors

Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn2+-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.

UV/Vis and fluorescence study on anthralin and its alkylated derivatives

Anthralin 1 and some of its C-10 or O-alkylated derivatives were investigated by UV/VIS- and fluorescence spectroscopy in different solvents and buffer systems, respectively. The effects of substituents on the formation of anthralin anion as well as the constitution of the resulting anions confirm that C-H acidity at position 10 is necessary for the formation of a fully aromatic anionic form. It is concluded that the resulting anion 1a is the pharmacologically active species of the antipsoriatic anthralin. Tautomerism of the neutral molecule is not observable.