Discovery of Targets for Immune-Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha.

Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune-metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti-PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms. SIGNIFICANCE: BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms. This article is highlighted in the In This Issue feature, p. 517.

Total synthesis of the monoterpenoid alkaloid (±)-tangutorine.

A novel approach to a formal total synthesis of the monoterpenoid indole alkaloid (±)-tangutorine has been developed starting from an α,ß-unsaturated cyclic dehydroamino ester. Synthesis of the rather unusual trans-substituted 2,3-indoloquinolizidine substructure was accomplished via Cu(II)-mediated conjugate addition and organozinc/copper coupling as the key steps, thereby setting the stage for ring-closing metathesis to produce the quinolone substructure. Finally, Bischler-Napieralski cyclization gave rise to the pentacyclic system of (±)-tangutorine thereby realizing a formal synthesis in an overall yield of 5.2% in eight consecutive steps.