Penetration of crustal melt beyond the Kunlun Fault into northern Tibet

The weak lithosphere of the Tibetan plateau is surrounded by rigid crustal blocks1 and the transition between these regimes plays a key role in the ongoing collision between India and Eurasia. Geophysical data2,3,4,5 and magmatic evidence6,7 support the notion that partial melt exists within the anomalously hot7,8 crust of northern Tibet. The Kunlun Fault, which accommodates the plateau’s eastward extrusion, has been identified as a significant rheological boundary4 between weak, warm Tibetan crust8 and the rigid eastern Kunlun–Qaidam block. Here we present reanalyses and remodelling of existing magnetotelluric data4, using an anisotropy code9 to obtain revised resistivity models. We find unequivocal evidence for anisotropy in conductivity at the northern edge of the Tibetan plateau. We interpret this anisotropy as the signature of intrusion of melt that penetrates north from the Tibetan plateau and weakens the crust beneath the Kunlun Shan. We suggest that our identification of a melt intrusion at the northern edge of the Tibetan plateau compromises the previous identification of the Kunlun Fault as an important rheological boundary. We conclude that the crustal melt penetration probably characterizes the growth of the plateau10 to the north, as well as accommodating the north–south crustal shortening in Tibet

The Resilience of the Nation State: Cosmopolitanism, Holocaust Memory and German Identity

Welch S, Wittlinger R. Die Widerstandsfähigkeit des Nationalstaates: Kosmopolitismus, Holocaustgedächtnis und deutsche Identität. Natarajan R, tran.; In: Lehmann R, Öchsner F, Sebald G, eds. Formen und Funktionen sozialen Erinnerns. Soziales Gedächtnis, Erinnern und Vergessen – Memory Studies. Wiesbaden: Springer Fachmedien Wiesbaden; 2013: 187-202

Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors.

Specificity for a desired enzyme target is an essential property of small-molecule inhibitors. Molecules targeting oncogenic driver mutations in the epidermal growth factor receptor (EGFR) kinase domain have had a considerable clinical impact due to their selective binding to cancer-causing mutants compared to wild type. Despite the availability of clinically approved drugs for cancers driven by EGFR mutants, persistent challenges in drug resistance in the past decades have led to newer generations of drugs with divergent chemical structures. The present clinical complications are mainly due to acquired resistance to third-generation inhibitors by the acquisition of the C797S mutation. Diverse fourth-generation candidates and tool compounds with C797S selectivity have emerged and their structural characterization has allowed for understanding of the molecular factors that allow for EGFR mutant selective binding. Here, we have reviewed all known structurally-characterized EGFR TKIs targeting clinically-relevant mutations to identify consistent binding mode features that enable C797S inhibition. Newer generation EGFR inhibitors exhibit consistent and previously underutilized hydrogen bonding interactions with the conserved K745 and D855 residue side chains. We also consider binding modes and hydrogen bonding interactions of inhibitors targeting the classical ATP and the more unique allosteric sites

Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448)

Lazertinib (YH25448) is a novel third-generation tyrosine kinase inhibitor (TKI) developed as a treatment for EGFR mutant non-small cell lung cancer. To better understand lazertinib inhibition at the molecular level, we determined crystal structures of lazertinib in complex with both WT and mutant EGFR and compared its binding mode to that of structurally-related EGFR TKIs. We observe that lazertinib binds with the novel pyrazole moiety involved in hydrogen bonds and van der Waals interactions consistent with drug potency and T790M mutant selectivity. Biochemical assays and cell studies confirm that lazertinib effectively targets EGFR(L858R/T790M) and to a lesser extent against HER2 as consistent with an improved toxicity profile. The molecular basis for lazertinib inhibition of EGFR reported here highlights new strategies for structure-guided design of tyrosine kinase inhibitors

Pitfalls and considerations in determining the potency and mutant selectivity of covalent epidermal growth factor receptor inhibitors

Pursuing enzyme inhibitors with molecules that form covalent bonds with the desired target is an attractive focus in drug development that is increasing in prevalence. However, challenges arise when carrying out assessments of their time-dependent inhibitory properties as well as making correlations with values reported in the literature. Given the prominent focus on the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase in oncology, and the diverse structures and binding modes of covalent EGFR inhibitors, this perspective seeks to explore various broadly relevant factors that arise in the measurement of kinetic parameters within this class of drugs. A review of several studies indicates that variable literature potency values require investigators to include appropriate reference molecules and consistent substrate conditions for experimental consistency and proper benchmarks. The impact on covalent inhibitor potency with respect to common buffer conditions and compound liquid handling is surveyed highlighting the importance of multiple experimental variables when conducting these assays. Additionally, when assessing the potency for inhibitor selectivity in targeting EGFR mutants over wild-type (WT), it is ideal to consider ratios of true potency due to the variable ATP substrate binding affinities. The overview presented here, although most directly applicable to the tyrosine kinase inhibitor field, serves inhibitor assessments broadly by providing guided insights into conducting biochemical assays for designing and validating next-generation covalent inhibitors

The origin of potency and mutant-selective inhibition by bivalent ATP-allosteric EGFR inhibitors

Targeted small-molecule therapies in mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) have undergone several generations of development in response to acquired drug resistance. With the emergence of the highly prevalent T790M and C797S drug-resistant mutations, a diverse arsenal of ATP-competitive molecules has led to the front-line drug AZD9291 (osimertinib) and several in clinical development. Several allosteric inhibitors bind a site adjacent to the ATP-binding site and exhibit synergy when dosed in combination with certain ATP-competitive inhibitors. Structure-guided design of molecules that anchor to both sites simultaneously, namely ATP-allosteric bivalent inhibitors, have been reported as proof-of-concept EGFR mutant-selective compounds, however their properties are underexplored and currently exhibit modest activity in human cancer cell lines. To better understand the structural and functional properties of such molecules, we have carried out structure-activity relationships (SAR) defining the groups of the allosteric pocket that are responsible for enabling mutant selectivity and potency of this series. We find that the back pocket phenol ring enables stronger binding while the methylisoindolinone is responsible for enabling selectivity for the oncogenic mutations. An optimized allosteric site-binding group and a C797-targeting ATP-site scaffold exhibit inhibitory effects in a variety of EGFR mutant cell lines, which is improved over earlier examples. Additionally, a closely related reversible-binding analogue exhibits mutant-selective activity and ~1 nM biochemical potency against L858R/T790M/C797S and promising antiproliferative effects in human cancer cells indicating that ATP-allosteric bivalent kinase inhibitors may serve as tool compounds in understanding overcoming these important resistance mechanisms. These results highlight the utility of bivalent ATP-allosteric compounds in understanding the impact certain functional groups have in the potency and mutant-selectivity enabled by allosteric pocket binding. The results of this study incentivize further investigations of compounds that bind within an exit vector made accessible in the inactive αC-helix “out” conformation as a novel approach for kinase inhibitors