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Between 1988 and 1993, 16 cases of osteoid osteoma were examined by magnetic resonance imaging (MRI). MRI clearly visualized the extent of inflammation in the bone marrow and soft parts that is difficult to observe with other diagnostic techniques. The degree of inflammation varied among the patients. This might be associated with the anatomical relationship between the nidus and the cortex. The high sensitivity of MRI, unfortunately, may lead to an erroneous interpretation in lesions accompanied by inflammatory responses of the bone marrow or soft parts, such as osteoid osteoma. However, these reactions on MRI may offer a key to the pathogenesis of osteoid osteoma, a unique bone neoplasm.

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

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