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LB-100 (3-(4-methylpiperazine-1-carbonyl)7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is a promising antitumor drug currently in early stage clinical testing. LB-100 has cytotoxic activity against a variety of cancer cells in culture and marked anti-tumor activity in animal models of tumor development. Phase I clinical studies (NCT01837667) concluded that the safety parameters of LB-100 support continued development [1]. Phase Ib/II trials (NCT0388662 and NCT03027388), which will assess the safety and efficacy of LB-100 against myelodysplastic syndromes and recurrent glioblastomas (astrocytoma, glioblastoma multiforme, and giant cell glioblastoma) respectively, are ongoing. Early reports revealed that LB-100 acts as a catalytic inhibitor of serine/threonine phosphatase 2A (PP2AC: encoded by PPP2CA/PPP2CB). More recently, LB-100 was shown to also target PPP5C, inhibiting PP2AC and PPP5C with similar potency (IC50 = 0.4 and 1.8 μM for PP2AC and PPP5C, respectively) [2]. To determine the molecular basis for catalytic inhibition, we solved the high-resolution crystal structure of PPP5C in the presence of LB-100 at a resolution of 1.65 Å, which revealed clear electron density for the 7-oxabicyclo[2.2.1]heptane-2,3dicarbonyl moiety, with the 2,3-dicarbonyl of LB-100 coordinating with both catalytic metals (M1 and M2). In order to accommodate the inhibitor, the side chains of Arg275 and Tyr451 adopt alternate conformations in relation to the active site metals, and the O7 bridgehead oxygen replaces the water molecule, which would otherwise coordinate with metal ion, M2. This causes the inhibitor to be tightly coordinated within the catalytic pocket, blocking substrate access to the catalytic metals (Figure 1). However, in our high-resolution structure [2], there is no density for the 3-(4-methyl-1-piperazine) ring, Editorial

Targeting phosphatases in cancer: suppression of many versus the ablation of one