BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2­(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.

PARP1 inhibitors (PARPis) are used clinically during cancer therapy and are thought to exert their cytotoxicity through PARP1 polymerase inhibition and PARP1‐DNA trapping. Here, we showed no significant correlation between PARP1‐DNA trapping and cytotoxicity induced by PARPis. We complemented PARP1‐knockout sublines with wild‐type PARP1 and 11 mutants with different point mutations that affect the polymerase activity. When examining the PARPi talazoparib, the induced cytotoxicity was highly significantly correlated with cellular PARP1 polymerase activity, but not with its PARP1‐DNA trapping or polymerase inhibition. Similarly, talazoparib's PARP1‐DNA trapping revealed significant correlation with the polymerase activity rather than its inhibition. Differently, however, when evaluating purified wild‐type and mutated PARP1, we identified an almost linear relationship between PARPis’ inhibiting PARP1 dissociation from DNA and their cytotoxicity in 17 cancer cell lines. In contrast, no significant correlation existed between PARP1 polymerase inhibition in the histone‐based systems and the cytotoxicity. After careful comparisons on different methods and detection targets, we conclude that the PARPi‐mediated increase in PARP1‐DNA binding by inhibiting autoPARylation of PARP1 on DNA rather than in PARP1‐DNA trapping is correlated with PARPi's cytotoxicity. Accordingly, we established a new PARPi screening model that more closely predicts cytotoxicity.

LMW heparin fractions obtained from various sources must not be considered as bioequivalent in both the in vitro and in vivo responses. Because of compositional variations, these agents exhibit individual behavior and should be considered as distinct drugs whose safety and efficacy profile must be determined separately. Currently, there is no valid LMW heparin standard available, however, different LMW heparins can be profiled in identical test systems. It is erroneous to assume that most LMW heparins will behave in a similar fashion in terms of safety and efficacy. The need for defined tests to characterized these agents is evident and efforts to profile their actions should be made at both the basic and applied levels. Needless to say, the true efficacy of LMW heparins can only be validated in well-designed randomized clinical trials. Optimization of LMW heparins in preclinical pharmacologic studies, as reported here, is a crucial factor in the development of these agents. The superior clinical efficacy/safety performance of some of the LMW heparins in contrast to other LMW heparins is a result of extensive preclinical pharmacologic investigations undertaken to optimize the therapeutic index of these agents. Such optimization studies have not been conducted during the development of many LMW heparins, resulting in decreased efficacy and undue complications.

A detailed chemical investigation of two South China Sea nudibranchs Phyllidiella pustulosa and Phyllidia coelestis, as well as their possible sponge-prey Acanthella cavernosa, led to the isolation of one new nitrogenous cadinane-type sesquiterpenoid xidaoisocyanate A (1), one new naturally occurring nitrogen-containing kalihinane-type diterpenoid bisformamidokalihinol A (16), along with 17 known nitrogenous terpenoids (2–15, 17–19). The structures of all the isolates were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. In addition, the absolute stereochemistry of the previously reported axiriabiline A (5) was determined by X-ray diffraction (XRD) analysis. In a bioassay, the bisabolane-type sesquiterpenoids 8, 10, and 11 exhibited cytotoxicity against several human cancer cell lines.