Maria-Elena Liosi

The Suzuki–Miyaura cross-coupling reaction is a cornerstone of C–C bond formation. However, heteroaryl boronic acids such as pyridyl and quinolyl derivatives remain challenging nucleophiles due to facile protodeboronation. Strategies enabling these substrates are limited to C(sp2)–C(sp2) formation. Efficient and modular C(sp2)–C(sp3) cross-coupling methods that directly employ these substrates remain underdeveloped. Here, we report a cross-organoboron platform that enables direct C(sp2)–C(sp3) bond formation from heteroaryl and alkyl organoboron reagents under visible-light irradiation using Ag2O/TiO2 nanoparticles (NPs). The two organoboron reagents undergo distinct Ag2O NP activations: alkyl boronates undergo single-electron photo-oxidation to generate alkyl radicals while arylboronates undergo transmetalation. Importantly, this method tolerates protodeboronation-prone pyridyl, quinolyl, α-heteroaryl boronic acids, and (hetero)aryl halide-containing substrates, including aryl iodides. High-throughput evaluation across 161 pharmaceutically relevant organoboron substrates identified 113 detectable couplings, and representative examples were validated at preparative scale. This work establishes photochemical cross-organoboron coupling as a complementary approach to classical transition-metal-catalyzed coupling and expands the accessible chemical space of heteroaryl organoboron reagents.

JAK2 is a non-receptor tyrosine kinase that regulates hematopoiesis through the JAK-STAT pathway. The pseudokinase domain (JH2) is an important regulator of the activity of the kinase domain (JH1). V617F mutation in JH2 has been associated with the pathogenesis of various myeloproliferative neoplasms, but JAK2 JH2 has been poorly explored as a pharmacological target. In light of this, we aimed to develop JAK2 JH2 binders that could selectively target JH2 over JH1 and test their capacity to modulate JAK2 activity in cells. Toward this goal, we optimized a diaminotriazole lead compound into potent, selective, and cell-permeable JH2 binders leveraging computational design, synthesis, binding affinity measurements for the JH1, JH2 WT, and JH2 V617F domains, permeability measurements, crystallography, and cell assays. Optimized diaminotriazoles are capable of inhibiting STAT5 phosphorylation by both WT and V617F JAK2 in cells.

Janus kinases (JAKs) are non-receptor tyrosine kinases that are essential components of the JAK-STAT signaling pathway. Associated aberrant signaling is responsible for many forms of cancer and disorders of the immune system. The present focus is on the discovery of molecules that may regulate the activity of JAK2 by selective binding to the JAK2 pseudokinase domain, JH2. Specifically, the Val617Phe mutation in JH2 stimulates the activity of the adjacent kinase domain (JH1) resulting in myeloproliferative disorders. Starting from a non-selective screening hit, we have achieved the goal of discovering molecules which preferentially bind to the ATP binding site in JH2 instead of JH1. We report the design and synthesis of the compounds and binding results for the JH1, JH2, and JH2 V617F domains, as well as five crystal structures for JH2 complexes. Testing with a selective and non-selective JH2 binder on the autophosphorylation of wild-type and V617F JAK2 is also contrasted.