Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.

Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.

We describe the rational design and synthesis of B- and A, B-ring-modified camptothecins. The key alpha-hydroxy-delta-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t(1/2) of 130 min and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.

A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12)(13)(14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, non-aromatic C5-substituents was also explored and revealed that the K i follows a well-defined correlation with the Hammett σ p constant (ρ = 3.01, R 2 = 0.91) in which electron-withdrawing substituents enhance potency leading to inhibitors with K i 's as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.Fatty acid amides are an important new class of lipid signaling molecules that modulate a number of physiological processes. Two endogenous fatty acid amides, anandamide (1a) 1 and oleamide (1b), 2-4 have emerged as prototypical members of this class that serve as chemical messengers (Figure 1). Anandamide (1a), which was only discovered a little more than a decade ago and is the most recognizable member of the endogenous fatty acid ethanolamides, 5 binds and activates both the central type-1 (CB1) and peripheral type-2 (CB2) cannabinoid receptors. Anandamide (1a), and members of the cannabinoid family, 6 have been implicated in the modulation of nociception, 7-9 feeding, 10,11 emesis, anxiety, 12 cell proliferation, 13,14 inflammation, 15 memory 16 and neuroprotection after brain injury. 17 Thus, the cannabinoids have clinical relevance for analgesia, anxiety, epilepsy, cachexia, cancer, and Alzheimer's disease as well as other neurodegenerative diseases. 18-20 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOleamide (1b) was found to accumulate in the cerebrospinal fluid of animals under conditions of sleep deprivation and to induce physiological sleep in a dose dependent manner where it reduced motility, shortened the sleep induction period, and lengthened the time spent in slow wave sleep 2 at the expense of wakening. 2,4 In a structurally specific manner, it was found to modulate serotonergic systems 21-23 and GABAergic transmission, 24,25 block glial gap junction cell-cell communication, 26,27 decrease body temperature and locomotor activity, 28 and exhibit the characteristic in vivo analgesic and cannabinoid behavorial effects of anandamide, 21,29 albeit without direct cannabinoid receptor activation. It has been suggested that the cannabinoid behavorial effects of oleamide (1b) may be mediated through an as yet unknown distinct pharmacological target. 24 Because oleamide (1b) may play a critical role in sleep, it may provide an exciting therapeutic potential for the development of sle...

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Chiral ketone cyanohydrins are important and versatile synthetic intermediates, which can be easily converted to R-hydroxy carbonyl compounds that contain chiral quaternary stereocenters. 1,2 Recently, we have developed a novel chiral ligand 1 derived from D-glucose and found that the Ti-1 complex catalyzes a highly

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The concurrent implementation of a proteome-wide serine hydrolase selectivity screen with traditional efforts to optimize fatty acid amide hydrolase inhibition potency leads to the expedited discovery of a new class of exceptionally potent and unusually selective inhibitors (I) with a 1,3,4-oxadiazole skeleton. The synthesis is outlined and the screening procedure is described. -(LEUNG, D.; DU, W.; HARDOUIN, C.; CHENG, H.; HWANG, I.; CRAVATT, B. F.; BOGER*, D. L.; Bioorg. Med. Chem. Lett. 15 (2005) 5,