A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 μM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.

Ligand‐based NMR screening represents a powerful method in fragment‐based drug discovery for the identification of chemical matter interacting with the receptor of interest. The large dynamic range of these methods allows the detection of weakly binding ligands. However, the methodology has not been extensively used for quantifying the strength of these interactions. This knowledge is important for ranking fragments according to their binding strength and for prioritizing structure‐based and medicinal chemistry activities. Rapid NMR methods for measuring the dissociation constant in direct and competition modes are presented here. The theory underpinning these methods are presented, along with their application to the measurement of the binding affinities of several ligands of the heat shock protein 90.

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YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferation. Aberrant activation of YAP1 has been reported for multiple tumor types and inhibiting the interaction of YAP1 with its partner protein TEAD is thought to be a means of targeting aberrant YAP1 activity. In order to identify small molecule inhibitors of YAP1 interaction with TEAD, we have performed a fragment-based-screening looking for ligands binding to TEAD at its interface with YAP1 (TEAD pocket S3). We have employed three techniques for fragment screening (NMR, SPR, DSF) and have cross tested positive hits identified by one technique with the respective orthogonal method. Using this strategy on Sanofi proprietary fragment libraries, three different fragment series have been identified. X-Ray co-structures with TEAD have been obtained for all three fragment series confirming binding to the S3 pocket of TEAD. Binding mode determination by X-Ray crystallography has set the stage for subsequent fragment optimization. Citation Format: Laure Delarbre, Olivier Venier, Iris Valtingojer, Jacques Houtmann, Maryse Lowinski, Annick Parent, Françoise Bégassat, Angelique Lasbleiz, Catherine Seys, Philippe Bombart, Laurent Debussche, Alexey Rak. Using a fragment based approach for the identification of TEAD S3 pocket binders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4867.

y -Oncomagazine -trimestriel août 2010 -Vol. 4 -n° 3 soignants sont-ils persuadés qu'elle est dans l'erreur ? Pourquoi cet empressement à vouloir les « reconstruire », et vite ? N'y aurait-il pour eux aucune autre alternative qui vaille d'être prise en compte ? Cette dernière hypothèse pose la question de la représentation, dans le milieu hospitalier, de la femme qui a eu une ablation du sein. Pour nous éclairer, nous avons demandé à deux infirmières ce qu'on leur a enseigné à ce sujet pendant leurs études. Laura vient de passer avec succès ses examens, Monique, maintenant à la retraite, a été élève infirmière en 1960. En 50 ans, quelle a été l'évolution de cet enseignement ? 1961 : « Ne les laissez pas partir, elles ne reviennent pas ! » J'étais alors à l'école d'infirmières à Beaune. La présentation et les traitements des différents cancers existants faisaient partie des programmes d'études, dont le cancer du sein.