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Several oncogenic drivers have been identified in non-small cell lung cancer. Targeted therapies for these aberrations have already been successfully developed and implemented in clinical practice. Owing to improved sensitivity in genetic testing, more and more tumors with multiple driver mutations are identified, resulting in dilemmas for treating physicians whether and which targeted therapy to use. In this case series, we provide an overview of patients with intrinsic double mutations in oncogenic drivers and their reported response to targeted therapies, with a focus on epidermal growth factor receptor, anaplastic lymphoma kinase, cMET, and Kirsten rat sarcoma viral oncogene. We also include an unpublished case report on a patient with an epidermal growth factor receptor L858R and cMET exon 14 skipping.

Using several reactions that include homologations and asymmetric epoxidations as well as Ugi and Huisgen couplings, we generated a small focused library of new derivatives from the labdane-type diterpene grindelic acid. These compounds were evaluated as cytotoxic agents against a panel of five human solid tumor cell lines (HBL-100, HeLa, SW1573, T-47D, and WiDr). The presence of the diamide functionalizations enhanced the cytotoxic effect. N-Benzyl-N-(1-(benzylamino)-2-methyl-1-oxopropan- 2-yl)grindelicamide, proved to be the most active product in all cell lines tested, with values of 0.95 (0.38) mM against HBL-100 cells. Fil: Reta, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Chiaramello, Alejandra Ilda. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Química. Area de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina Fil: García, Celina. Universidad de la Laguna. Departamento de Química Orgánica; España. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "Antonio Gonzalez"; España Fil: León, Leticia G.. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "Antonio Gonzalez"; España Fil: Martín, Víctor S.. Universidad de la Laguna. Departamento de Química Orgánica; España. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "Antonio Gonzalez"; España Fil: Padrón, José M.. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "Antonio Gonzalez"; España Fil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Donadel, Osvaldo Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto de Investigaciones en Tecnología Química; Argentina

A Phenotypic Drug Discovery strategy was applied to study a set of pyrimidine analogs prepared by means of intramolecular oxidation-reduction reactions of N-substituted-N-(2,6-disubstituted-5-nitro-4-pyrimidinyl) aminoacetic acid methyl esters in basic media. The combined and rational use of specific assays allowed in short time reducing from all possible cellular targets to those involved in metaphase to anaphase transition. © 2011 Elsevier Ltd. All rights reserved., Co-financed by the European Social Fund (FEDER): the Spanish MICINN (CTQ2008-06806-C02-01/BQU), the Spanish MSC (RTICC RD06/0020/1046 and RD06/0020/0041), the Canary Islands ACIISI (PI 2007/021), the Canary Islands FUNCIS (PI 43/09), and by the Lithuanian Research Council: Global Grant Programme (Grant No. VP1-3.1-SMM-07-K-01-002). L.G.L. thanks the Spanish MSC-FIS for a Sara Borrell contract.

The biological evaluation of new Ru(II) complexes carrying dmoPTA (dmoPTA=3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) ligands is reported. The results on the biological activity revealed that the organometallic complexes are active against all cell lines with GI(50) values in the range 1.1-2.6 μM. When compared to the standard anticancer drug cisplatin, the bimetallic Ru(II) complexes showed a greater activity profile. The cell cycle analysis revealed that the new compounds induced arrest in G(1) phase. Contrary to cisplatin, these Ru(II) complexes do not interact with DNA. This result suggests that DNA might not be the key pharmacological target.

A series of analogs were synthesized in a straightforward manner from naturally available sesquiterpenes ilicic acid and tessaric acid. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D and WiDr. The most potent analog induced considerably growth inhibition in the range 1.9-4.5 microM. Cell cycle studies for tessaric acid derivatives indicated a prominent arrest of the cell cycle at the G(2)/M phase. Damage to the cells was permanent as determine by the so called 24+24 drug schedule.

A series of 2,4-disubstituted 6-aryl-7 H -pyrrolo[3,2- d ]pyrimidin-7-one 5-oxides were synthesized and in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, HBL-100, HeLa, SW1573, T-47D, and WiDr. The most potent analog induced considerably growth inhibition in the range 0.35–2.0 μM. Cell cycle studies in the breast and lung cancer cells revealed arrest in the G 2 /M compartment. The results showed that the title compounds bearing alkylamino or dialkylamino moieties in position 2 of the pyrimidine ring are more active than those bearing hydrogen or methylthio groups.

A series of trans-2-alkyl-4-halopiperidines and 2-alkyl-4-halo-1,2,5,6-tetrahydropyridines were prepared by means of an iron(III) catalyzed process. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). The results on the biological activity revealed that, in general, the 2-alkyl-4-halo-1,2,5,6-tetrahydropyridine analogs are more potent than the trans-2-alkyl-4-halopiperidine derivatives. A remarkable selectivity of the aza compound 5f for the resistant cell line WiDr was observed. Cell cycle studies revealed a G2/M phase arrest for 5f.

In this study, we synthesized a series of enantiomerically pure (2R,3R)-disubstituted tetrahydropyrans with diverse functional groups. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). Overall, the results show the relevance for antiproliferative activity of the α,β-unsaturated ester side chain at position 2 of the THP ring.

A series of cis-2,6-dialkyl-4-chloro-tetrahydropyrans were prepared by means of an iron(III)-catalyzed process. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, SW1573, and WiDr. The results show that the presence of bulky substituents favors the Prins cyclization leading to new products with better activity profile against all cell lines tested.

A set of γ-lactones α,β-fused and β,γ-fused to carbocycles have been synthesized and evaluated for their in vitro antiproliferative activities using the human cancer cell lines SW1573 (lung), T-47D (breast) and WiDr (colon). The compounds are obtained by intramolecular ring closing metathesis of the corresponding dienes. Active compounds exhibited GI 50 values in the range 8–18 μM. A structure–activity relationship is also discussed.