Doctor of Philosophy, Colorado State University (2014)
Bachelor of Science, University of California Santa Cruz (2004)
Associate of Arts, De Anza College (2002)
Pharmacologic expansion of endogenous ?-cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control ?-cell growth we screened ?2,400 bioactive compounds for rat ?-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat ?-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase (JNK) inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) ?-cell replication via dual specificity tyrosine-phosphorylation-regulated kinases (DYRK1A/B) inhibition. In contrast to rat ?-cells, which were broadly growth responsive to compound treatment, human ?-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3? (GSK-3?) or transforming growth factor-? (ALK5/TGF-?) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T-cells (NFAT) as the primary mechanism of human ?-cell replication induction. However, inhibition of NFAT activity had limited impact on CC-401-induced ?-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the ?-cell replication-inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control ?-cell replication and leverage a novel DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control ?-cell growth.
View details for DOI 10.1210/en.2018-00083
View details for PubMedID 29514186
Formal syntheses of tetracyclic terpenoids frondosin B and liphagal are described. Both synthetic routes rely on the use of platinum-catalyzed ?,?-unsaturated carbene formation for the key C-C bond forming transformations. The successful route toward frondosin B utilizes a formal (4 + 3) cycloaddition, while the liphagal synthesis features the vinylogous addition of an enol nucleophile as a key step. Both synthetic routes are discussed, revealing insights into structural requirements in the catalytic ?,?-unsaturated carbene reaction manifold.
View details for DOI 10.1021/acs.orglett.6b03682
View details for Web of Science ID 000391781600075
View details for PubMedID 27997203
View details for PubMedCentralID PMC5369019