Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

The Lago della Vecchia-Valle d'Irogna rocks are part of the Eclogitic Micaschists Complex (EMC) of the Sesia-Lanzo Zone, western Austroalpine domain. The 1:10,000 scale map includes metaintrusive, minor micaschist, banded gneiss, and metabasic boudins. The multiscale structural analysis reveals successive magmatic and tectono-metamorphic stages: during M0 the metaintrusive protoliths emplaced; D1 took place under eclogite-facies conditions; during D2 stage, a pervasive foliation developed under retrograde blueschist-facies conditions; D3-D4 and D5 structures developed under greenschist-facies conditions; during M6 andesitic dykes intruded. The mapped degree of fabric evolution (FE) and metamorphic transformation (MT) related to D2-foliation shows that the MT was not only controlled by bulk rock and mineral compositions, but also by FE. The development of a pervasive blueschist-facies D2-foliation is in contrast with the eclogitic dominant fabric generally recorded in the EMC. This difference suggests that FE and MT are potentially responsible for km-scale heterogeneities in the tectono-metamorphic record.ARTICLE HISTORY

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Geological mapping, multiscale structural analysis, and estimations of the degree of fabric evolution and of reaction progress allow the construction of a 3D quantitative model of structural and metamorphic gradients in a portion of continental crust deeply involved in the Alpine subduction system and mainly structured under eclogite-facies conditions before the continental collision. The investigated and modelled rocks outcrop in the surroundings of Mt. Mucrone, in the central Sesia-Lanzo Zone. The Geomodeller ® software allowed a quantitative 3D estimation of domains characterized by homogeneous fabric evolution and metamorphic reaction progress (DFE and DRP, respectively) for two of the seven structural and metamorphic imprints detected in this area: the D2-eclogitic and D5-greenschist stages, which are the most pervasive at km scale. Such a 3D modelling clarifies mutual relationships between fabric and metamorphic gradients and indicates that: (i) DFE and DRP are closely related regardless of the rock type; (ii) the syn-deformational thermal regime can influence the degree of metamorphic transformation, if DFE remains below the 60% threshold; (iii) the phase transitions can not be properly implemented in quantitative geodynamic modelling without considering the heterogeneity of reaction progress and fabric evolution.