Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

We provide an overview and comparison of predictive capabilities of several methods for ranking association football teams. The main benchmark used is the official FIFA ranking for national teams. The ranking points of teams are turned into predictions that are next evaluated based on their accuracy. This enables us to determine which ranking method is more accurate. The best performing algorithm is a version of the famous Elo rating system that originates from chess player ratings, but several other methods (and method versions) provide better predictive performance than the official ranking method. Being able to predict match outcomes better than the official method might have implications for, e.g., a team's strategy to schedule friendly games.

The mechanism of the formation of a 2 ions from b 2 ions occurring during fragmentation of protonated peptides is investigated using quantum chemical methods. The geometries of the stationary structures involved in two possible mechanisms, namely, a two-step mechanism via an open-chain acylium ion and a concerted pathway involving rupture of two covalent bonds of the cyclic isomer of the b 2 ion, as well as the energetics of the reactions, were calculated at the MP2 and B3LYP levels, both combined with the 6-31G ( Mass spectrometry has become a valuable tool for peptide and protein research in the last few years. This is mainly due to the development of 'soft' ionization methods such as matrix-assisted laser desorption 1 (MALDI) and electrospray ionization 2-4 (ESI), which allow the formation of singly or multiply charged peptides and proteins in the gas phase. Because of the complexity and the enormous amount of fragmentation data, mass spectrometric sequencing of proteins relies on the extensive use of sequencing programs and protein/DNA databases.In spite of the importance of mass spectrometry in protein analysis, fragmentation of protonated peptides is understood only at the empirical level, 5-9 and the fine details of the fragmentation pathways are still not known. This is, however, not very surprising since the mass spectra of protonated peptides are usually too complicated to unambiguously assign all the peaks and rarely provide very detailed structural information on the investigated species. However, the missing energetic and structural data can be obtained in a straightforward way from the results of quantum chemical calculations. Recently, we have started a systematic work to determine the characteristics of the most important fragmentation reactions occurring during mass analysis of protonated peptides by means of theoretical methods. In a recent article, 10 we investigated the formation of b 2 ions from protonated N-formylglycinamide and AcAla-NH 2 by using high level quantum chemical methods.The calculated reaction mechanism revealed the atomic details of b 2 ion formation involving a simultaneous ring closure and the departure of an NH 3 molecule. The calculated energetics were in excellent agreement with the experimentally observed small excess energy released as kinetic energy during the dissociation. Using high level ab initio methods we have shown that formation of the b 2 ions takes place through a barrier of approximately 10 kcal mol À1 , and leads to the formation of an ion-molecule complex. The energy of the transition structure is well below the energy level of the separated b 2 ion plus NH 3 . The goal of the present article is to reveal the atomic details of another important dissociation, namely, the b 2 → a 2 reaction. The a n ions are usually abundant constituents of the mass spectra of protonated peptides provided that b n ions are formed during the dissociation of the backbone amide groups. The formation of a 2 ions has previously been investigated by using both experimental 11 and ...

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information. The introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanismbased cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.