Kumar Dilip Ashtekar

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) with important roles in many cellular processes as well as cancer and other diseases. EGF binding promotes EGFR dimerization and autophosphorylation through interactions that are well understood structurally. However, it is not clear how these dimers relate to higher-order EGFR oligomers detected at the cell surface. We used single-particle tracking (SPT) and Förster resonance energy transfer (FRET) imaging to examine how each domain within EGFR contributes to receptor dimerization and the rate of its diffusion in the cell membrane. We show that the EGFR extracellular region is sufficient to drive receptor dimerization, but that the EGF-induced EGFR slow-down seen by SPT requires formation of higher order oligomers, mediated in part by the intracellular tyrosine kinase domain – but only when in its active conformation. Our data thus provide important insight into higher-order EGFR interactions required for EGF signaling.

This report presents a structure-guided approach for the optimization of VANOL-derived imidodiphosphorimidates as catalysts for the halonium-ion-induced spiroketalization reaction. Fine tuning of the catalyst active site, alongside enhanced acidity, were required to achieve high catalytic activity for the spiroketalization reaction. A wide range of substrates were well tolerated yielding halogenated spiroketals in high yields, diastereoselectivities, and enantioselectivities.

Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and lowK_{M, ATP}). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.

Employing halenium affinity (HalA) as a guiding tool, the weak nucleophilic character of alkyl ketones was modulated by the templating effect of a tethered 2‐tetrahydropyranyl(THP)‐protected alcohol towards realizing a bromenium ion initiated spiroketalization cascade. Addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals. Alternatively, exclusion of ethanol from the reaction mixture biased the transient oxocarbenium towards α‐deprotonation that precedes a second bromofunctionalization event thus, furnishing dibrominated spiroketals. The regio‐ and stereoselectivity exploited in the current methodology provides a novel and rapid access to the dibrominated spiroketal motifs exhibited by several natural products.

Employing halenium affinity (HalA) as a guiding tool, the weak nucleophilic character of alkyl ketones was modulated by the templating effect of a tethered 2‐tetrahydropyranyl(THP)‐protected alcohol towards realizing a bromenium ion initiated spiroketalization cascade. Addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals. Alternatively, exclusion of ethanol from the reaction mixture biased the transient oxocarbenium towards α‐deprotonation that precedes a second bromofunctionalization event thus, furnishing dibrominated spiroketals. The regio‐ and stereoselectivity exploited in the current methodology provides a novel and rapid access to the dibrominated spiroketal motifs exhibited by several natural products.