Research in the Fuchs lab spans both cancer and infectious disease related projects. These applications require us to design and synthesize molecules capable of affecting key proteins or pathways involved in disease progression. We also focus on the optimization of drug properties in these molecules in an effort to affect drug properties, including improvement of solubility or reduction of metabolism. The projects below illustrate our contributions to highly collaborative projects in these areas.

Anticancer Agents of Diverse Natural Origin

The program project grant P01 CA125066 serves as a multi-institutional platform for the discovery and development of potential therapeutics from natural sources, including plants, cyanobacteria, and fungi, for applications in cancer. It brings together researchers with a variety of specializations, including natural products isolation, assay development, cancer biology, lead optimization, and pharmacokinetics. The role of the Fuchs lab on this project is to aid in the development of promising natural products through structural derivatization, property optimization, and the synthesis of probe molecules for mechanism of action studies.

Two of the molecules of interest identified as a part of this program are scytonemide A, a unique cyclic imine with activity against the proteasome, and phyllanthusmin D, an arylnaphthalene lignan lactone with very high potency against a variety of cancer cells. Our recently completed synthesis of scytonemide A utilized a solid phase synthesis approach employing the Weinreb AM resin (J. Nat. Prod. 2018, 534). This practical synthesis has facilitated the further testing of the biological properties of this compound and its structural analogues. Our work on phyllanthusmin D has focused on understanding the structure-activity relationships for the arylnaphthalene lignan lactone class (Bioorg. Med. Chem. 2018, 2354) and investigation of the underlying mechanism of action for these compounds (Mol. Cancer Ther. 2018, 2123). PHY-34, one of the most potent structural derivatives synthesized in our lab thus far, has demonstrated promising results in both in vitro and in vivo models and has been shown to act as a late-stage autophagy inhibitor.

Allosteric Inhibitors of HIV-1 Integrase

Another collaborative effort involves work on HIV-1 integrase (IN) with the lab of Dr. Mamuka Kvaratskhelia. The project focuses on the development of compounds that are capable of binding to the allosteric LEDGF/p75 site of IN at the IN CCD dimer interface. This binding ultimately causes hyper-multimerization of IN and leads to the formation of eccentric virions and a profound effect on virus particle maturation. A number of different scaffolds have been investigated for their ability to inhibit IN activity through binding to the CCD dimer interface of IN and the recruitment of an additional IN unit. These molecular probes have helped to refine the mechanism through which compounds of this type act and highlight the key role that IN plays in the viral life cycle.