The cyclopalladation of a series of symmetric diimines with the formula (RC 6 H 4 CHNZ) 2 , where Z = CH 2 or (CH 2 ) 2 OCH 2 and R = p-Cl, p-OMe, p-NO 2 , and o-Cl, is described. Optimal conditions to obtain the dimetalated compounds were found to be palladium(II) acetate, in toluene, at 60 °C and with a reaction time of 2−4 h. The reactivity of the dimetalated compounds with monodentate, bidentate, and bis(monodentate) Lewis bases was also studied. The cytotoxic activity of some selected compounds was evaluated against a panel of adenocarcinoma cell lines (colon HCT116 and breast MCF7 and MDA-MB231). Compounds containing the fragment NCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 N exhibited a remarkable cytotoxic activity in the three cancer cells assayed, but complexes containing the NCH 2 CH 2 N fragment showed no activity. It seems that the length and flexibility of the central saturated chain in the imine molecule, as well as its lipophilicity and hydrophilicity, explain the different cytotoxicity of the two series of coordination compounds here reported.

The synthesis and characterization of two families of cyclometalated Ru(II) complexes with the new (C sp 2 ,N indole ) − motif formed by activation of the C−H bonds of 2-phenylindole ligands of the general formula {(4′-R 1 -C 6 H 4 )-3-NOMe-5-R 2 -6-R 3 -(C 6 H 2 N)} are presented. The novel ruthenacycles show a remarkable cytotoxic activity in MCF7 and MDA-MB231 breast cancer cell lines, which clearly exceeds those of the trans and cis isomers of [PtCl 2 (L)(DMSO)] derived from the same ligands and even that of cisplatin.

MYC is a transcription factor involved in fundamental cellular functions such as proliferation, apoptosis, differentiation, metabolism and, as lately discovered, immune response. [1,2] It is deregulated in a wide variety of aggressive human cancers and its overexpression is one of the most common events associated with tumorigenesis, making it one of the most attractive yet challenging targets in oncology.[3] c-MYC protein structure is mostly disordered in its monomeric state, and assumes a helix-loop-helix fold upon binding to its protein partner MAX. The absence of clefts or hydrophobic pockets (typical of enzymes) and the large protein-protein interaction surface formed in the c-MYC/MAX complex represent a challenge for the design of small molecule inhibitors. Moreover, the intra-nuclear localization of c-MYC renders the use of antibodies impossible. Hence, it is not surprising that conventional drug development has failed and no therapeutic has yet progressed into clinical trials.[4] Here we describe IDP-121, a stapled peptide specifically designed to target c-MYC protein. A library based on c, l, n-MYC and MAX druggable regions was designed, with a bias towards disruption of c-MYC (residual) intra-protein interactions. The primary goal in the initial screen was to identify compounds able to block c-MYC's fold-like state that allows binding to MAX. A functional (cellular) assay was used for our screening program to ensure cell and nuclear penetration. Stapling technology was implemented to overcome the lack of stability and cell permeability common to unmodified peptides, whilst retaining c-MYC specificity and a large surface coverage. The lead compound, IDP-121, is stable to proteolysis and is rapidly internalized into cells, distributing efficiently into the nucleus (see Abstract 3). The interaction with c-MYC was characterized by HSQC-NMR, Fluorescence Polarization (FP) and Surface Plasmon Resonance (SPR). IDP-121 binds specifically to c-MYC, with a Kd of 400 nM, an affinity ten-fold higher than c-MYC/MAX interaction, allowing IDP-121 to displace MAX from the binding site. SAR studies were conducted to tailor the elements essential for its biological function. Isolated protein complex (ELISA), and pull-down and FRET experiments confirmed disruption of the c-MYC/MAX complex by IDP-121 (see Abstracts 2). The drug-like properties and efficacy in hematological and solid tumors of IDP-121 have been demonstrated in vivo (see Abstracts 2 and 3). In addition, IDP-121 has progressed through GLP toxicology studies without evidence of major systemic toxicity, allowing for the first viable Myc-targeted therapy to enter Phase 1 clinical trials in 2021. 1.Casey S.C. et al. Science 2016; 352 (6282): 227–231 2.Casey S.C. et al. Blood 2018; 131 (18): 2007-20153.Dang CV. Cell. 2012;149(1):22-35.4. Whitfield J. R., Front. Cell Dev. Biol. 2017 Citation Format: Carmen Calvis, Andreas Beier, Michael Feichtinger, Theresa Höfurthner, Miguel Moreno, Ramon Messeguer, Robert Konrat, Santiago Esteban, Laura Nevola. IDP-121, a first in class staple peptide targeting c-MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2471.