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Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.

The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identi®cation of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and su cient for production of pVHL18. pVHL18 can bind to elongin B, elongin C, and Hs-CUL2. When reintroduced into renal carcinoma cells that lack a wild-type VHL allele, pVHL18 suppresses basal levels of VEGF expression, restores hypoxiainducibility of VEGF expression, and inhibits tumor formation in nude mice. These data strongly support the existence of two distinct VHL gene products in VHL tumor suppression.

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DTs-ll is a highly diphtheria toxin (DT)-sensitive cell line previously isolated by transfection of wildtype DT-resistant mouse L-M(TK-) cells with the cDNA encoding a monkey Vero cell DT receptor. DTs-II (Mr 37,195). The cytotoxic action ofDT occurs by the following steps: (i) binding to specific cell-surface receptors, (ii) internalization of the (toxin-receptor) complexes into vesicles, and (iii) translocation of the A fragment from acidified vesicles into the cytosol, where it inhibits protein synthesis by ADP-ribosylation of elongation factor 2 (1-3).Our laboratory has recently used expression cloning to identify a receptor for DT (4). The gene encoding the receptor was cloned by transfecting wild-type toxin-resistant mouse L-M(TK-) cells with a cDNA library prepared from highly toxin-sensitive monkey Vero cells; the transfectants were screened for DT sensitivity employing a replica plate system that allowed for the detection of those mouse cells whose protein synthesis is inhibited upon exposure to DT and that, at the same time, preserved a "replica" ofthose cells (4,5

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