The discoipyrroles: A multifaceted approach to understand a novel family of marine natural products

Around 4 – 8% of patients with squamous cell carcinoma, the most prevalent subtype of non-small cell lung cancer (NSCLC), carry genetic mutations in discoidin domain containing receptor 2, or DDR2 (Hammerman, PS, Cancer Discovery 2011). This unique receptor tyrosine kinase binds collagen in the extracellular matrix and initiates signaling for cellular processes such as migration and adhesion. We discovered a novel family of natural products, the discoipyrroles, produced by the marine bacteria Bacillus hunanensis that demonstrate potent cytotoxicty towards DDR2 mutated NSCLC cell lines, but not DDR2 wildtype NSCLC cell lines (Hu, Y, JACS 2013). Currently, we are investigating multiple aspects of the discoipyrroles including their optimization as potential therapeutics, the mechanism by which they elicit cell-specific cytotoxicity, and their intriguing biosynthesis which features key non-enzymatic steps.

Tab. 1: Cytotoxicity to lung cancer cell lines

	HCC366*	H2286*	A549†	> 40 cell lines†
DPA	0.12	0.256	10.2	> 24
DPB	0.19	0.276	8.8	-
DPC	0.712	0.796	19.6	-
DPD	0.275	0.412	13.4	-
Dasatanib	0.17	-	9.8	-
*DDR2 mutant cell lines (HCC366: L293R; H2286: I638F). †DDR2 wildtype cell lines. IC50 in µM.