Mustapha Haddach

Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53

Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.

Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth

Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell- and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment.

Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer.

Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2s small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (K(i) = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.

A new method for the synthesis of ketones: The palladium-catalyzed cross-coupling of acid chlorides with arylboronic acids

The cross-coupling reaction of acid chlorides with arylboronic acids, using catalytic amounts of Pd(PPh3)4 and five equivalents Cs2CO3, under anhydrous conditions provides a new method for the synthesis of ketones in good to moderate yields.

Potential Use of Selective and Nonselective Pim Kinase Inhibitors for Cancer Therapy

Denis Drygin,† Mustapha Haddach,‡ Fabrice Pierre, and David M. Ryckman*,† †Cylene Pharmaceuticals, 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States ‡HTK Corporation, 5218 Rivergrade Road, Irwindale, California 91706, United States 3244 Caminito Eastbluff, Apt 40, La Jolla, California 92037, United States ■ INTRODUCTION Targeted agents and personalized medicine for cancer are the topics of much discussion and research in the medical community and pharmaceutical industry. Success in this area began with the first molecular target, the estrogen receptor, and its inhibitors such as tamoxifen (ICI 46474). Subsequently, a number of drugs have been approved that block oncogene induced signal transduction such as imatinib (STI 571) and others that affect proteins that regulate gene function exemplified by Vorinostat (SAHA). Other classes of targeted agents induce cells to undergo apoptosis like bortezomib (PS341) and a number of commercialized agents with function similar to that of sunitinib (SU 11248) were designed to block angiogenesis. Clearly, drugs designed to inhibit precise molecular targets or specific signaling pathways represent a valid approach for cancer therapeutics. Particularly, the deregulation of kinase function has emerged as a very active area of research, as it is one of the major mechanisms by which cancer cells avoid normal constraints on growth and proliferation. Additionally, the presence of an ATPbinding pocket makes these proteins easily amenable to medicinal chemistry efforts. In this Miniperspective we will discuss the inhibitors of the Pim kinase family that have been publically disclosed and their potential development as useful therapeutic agents in oncology. The Pim family has also been implicated in inflammation, and a Pim-1 inhibitor was shown to attenuate of allergen-induced airway hyper-responsiveness and inflammation; however, this is beyond the scope of this Miniperspective. The Pim kinases, Pim-1, -2, and -3, are a class of constitutively active serine/threonine kinases that are highly homologous (60−70%) in their kinase domains and have been implicated in several normal biological process including cell survival, proliferation, differentiation, and apoptosis. However, when these processes become disrupted or hyperactivated, they express several hallmarks of cancer. The name Pim arises from the original pim-1 gene as the proviral insertion site of the Moloney murine leukemia virus induced T-cell lymphoma. Pims are notably involved in signaling mechanisms associated with tumorigenesis. Mechanistic studies have shown that high expression levels of Pims are associated with hematologic and epithelial cancers in humans; thus, they can serve as potential therapeutic targets to address numerous unmet medical needs. Several classes of inhibitors have been described in the literature, and yet only two molecules have progressed to the clinic so far. It is noteworthy that for a long time, only inhibitors of Pim-1 were available despite the fact that increasing evidence suggests that all family members should be concurrently inhibited for optimal efficacy. For example, it has been shown that simultaneous inhibition of Pim-1 and Pim2 is necessary to overcome the oncogenic signaling by protein tyrosine kinases in leukemia. Only recently have examples of molecules able to modulate all isoforms (pan-Pim kinase inhibitors) been disclosed, representing one of the most interesting developments in the field. It is our desire to provide here a better understanding of the biology associated with Pimregulated signaling pathway and to promote additional research on these associated inhibitors to discover and develop compounds that have suitable drug properties and the ability to benefit patients. The concept of simultaneous inhibition of multiple pathways may have its roots in traditional combination chemotherapy but has applicability in targeted or multitargeted drug development as well. In fact, a significant proportion of the kinase inhibitors approved for cancer therapy today are multikinase targeting agents that are able to simultaneously modulate several biological processes of the disease. Although many of these drugs were not deliberately created for their multitargeting profile, a more rational design of molecules with multiple predefined targets has emerged. In this Miniperspective we will provide some discussion on the potential of the development of Pim kinase inhibitors with dialed in activity and selectivity properties to specifically target kinases known to be involved in cross-compensatory signaling for the disruption of cancer networks.

Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor.

Structure-activity relationship analysis in a series of 3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)amides identified compound 13, a pan-Pim kinases inhibitor with excellent biochemical potency and kinase selectivity. Compound 13 exhibited in vitro synergy with chemotherapeutics and robust in vivo efficacy in two Pim kinases driven tumor models.

Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics

Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pol I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.

Novel potent dual inhibitors of CK2 and Pim kinases with antiproliferative activity against cancer cells.

A novel family of potent dual inhibitors of CK2 and the Pim kinases was discovered by modifying the scaffolds of tricyclic Pim inhibitors. Several analogs were active at single digit nanomolar IC(50) values against CK2 and the Pim isoforms Pim-1 and Pim-2. The molecules displayed antiproliferative activity in various cell phenotypes in the low micromolar and submicromolar range, providing an excellent starting point for further drug discovery optimization.

Design and synthesis of tricyclic imidazo[4,5-b]pyridin-2-ones as corticotropin-releasing factor-1 antagonists.

The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.

Synthese et réactivité de nouveaux synthons perfluoroalkyles. Comportement atypique des azirines et aziridines F-alkylees

Abstract F -alkyl chains perturb the reactivity of substrates in an often unpredictable way. F -alkyl azirine and aziridine carboxylates were prepared from F -alkynylesters, in 80 and 60% yield, respectively, and were found to display reactivities different from those of their hydrocarbon analogs. Thus, F -alkylazirines ( 5 ) give addition products easily but resist ring opening, while the F -alkylaziridines ( 8 ) are extremely stable, both towards nucleophilic and electrophilic reagents and irrespective of the medium used, neutral, acid or basic.