Background-Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity. Methods and Results-Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose Key Words: heart failure Ⅲ apoptosis Ⅲ myocytes A nthracyclines such as doxorubicin, daunomycin, epirubicin, and idarubicin are widely used and highly successful anticancer chemotherapeutic drugs. Unfortunately, these drugs also induce acute cardiotoxicity, which is characterized by hypotension, tachycardia, arrhythmia, and transient depression of left ventricular function. [1][2][3][4] In addition, high cumulative doses are associated with late-onset cardiomyopathy that is refractory to standard treatment. It is widely thought that free radical-induced mitochondrial damage contributes to doxorubicin-induced cardiotoxicity. 5 In addition, doxorubicin can induce DNA damage, inhibit DNA and protein synthesis, promote myofiber degeneration, inhibit transcription of specific gene programs, and induce cardiomyocyte apoptosis via a caspase-3-dependent mechanism. Because doxorubicin can interfere with many different intracellular processes, it has proven difficult to determine the molecular mechanism of its acute and chronic cardiotoxicity. Clinical Perspective p 106Numerous studies have shown that doxorubicin-induced cardiomyocyte apoptosis is associated with increased expression of the p53 tumor suppressor protein. Moreover, reduction of p53 activity via genetic deletion 6 or chemical inhibition 7 is cardioprotective during short-term doxorubicin treatment. To further characterize the role of p53 in acute doxorubicin-induced cardiotoxicity, MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) 8 were studied 7 days after the initiation of treatment. Cardiac function was improved, with a concomitant reduction in cardiomyocyte apoptosis, in the MHC-CB7 mice compared with their doxorubicin-treated nontransgenic siblings. Surprisingly, expression of the MHC-CB7 transgene also markedly blunted the doxorubicin-induced reduction of cardiac mass observed in nontransgenic mice. Western blot analyses indicated that doxorubicin treatment reduced the level of activated mammalian target of rapamycin (mTOR) in nontransgenic mice. mTOR is a serine/threonine protein kinase that regulates protein translation and cell growth. 9 Expression of the MHC-CB7 transgene blocked doxorubicin-induced reduction of mTOR activity. To establish the role of mTOR signaling in doxorubicin-induced cardiotoxicity, mice expressing constitutively active mTOR in the myocardium (MHC-mTORca mice) 10 were subjected to doxorubicin treatment. Expression of the MHC-mTORca transgene was suffi...

Protein tyrosine phosphatases (PTPs) constitute a large family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. A detailed understanding of PTP functions in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific, cell-permeable small molecule agents. We present a stepwise focused library approach that transforms a weak and general nonhydrolyzable pTyr mimetic (F2Pmp, phosphonodifluoromethyl phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2, an antagonist of hepatic insulin signaling. The crystal structures of the PTP-MEG2-inhibitor complexes provide direct evidence that potent and selective PTP inhibitors can be obtained by introducing molecular diversity into the F2Pmp scaffold to engage both the active site and unique nearby peripheral binding pockets. Importantly, the PTP-MEG2 inhibitor possesses highly efficacious cellular activity and is capable of augmenting insulin signaling and improving insulin sensitivity and glucose homeostasis in diet-induced obese mice. The results indicate that F2Pmp can be converted into highly potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach, this strategy should be applicable to other members of the PTP superfamily.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF-and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAFand KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

Postnatal cardiac hypertrophies have traditionally been classified into physiological or pathological hypertrophies. Both of them are induced by hemodynamic load. Cardiac postnatal hypertrophic growth is regarded as a part of the cardiac maturation process that is independent of the cardiac working load. However, the functional significance of this biological event has not been determined, mainly because of the difficulty in creating an experimental condition for testing the growth potential of functioning heart in the absence of hemodynamic load. Recently, we generated a novel transgenic mouse model (␣MHC-BMP10) in which the cardiacspecific growth factor bone morphogenetic protein 10 (BMP10) is overexpressed in postnatal myocardium. These ␣MHC-BMP10 mice appear to have normal cardiogenesis throughout embryogenesis, but develop to smaller hearts within 6 weeks after birth. ␣MHC-BMP10 hearts are about half the normal size with 100% penetrance. Detailed morphometric analysis of cardiomyocytes clearly indicated that the compromised cardiac growth in ␣MHC-BMP10 mice was solely because of defect in cardiomyocyte postnatal hypertrophic growth. Physiological analysis further demonstrated that the responses of these hearts to both physiological (e.g. exercise-induced hypertrophy) and pathological hypertrophic stimuli remain normal. In addition, the ␣MHC-BMP10 mice develop subaortic narrowing and concentric myocardial thickening without obstruction by four weeks of age. Systematic analysis of potential intracellular pathways further suggested a novel genetic pathway regulating this previously undefined cardiac postnatal hypertrophic growth event. This is the first demonstration that cardiac postnatal hypertrophic growth can be specifically modified genetically and dissected out from physiological and pathological hypertrophies.Hypertrophic growth of cardiomyocytes plays an important role in determining the size of the heart (1, 2). Cardiomyocyte hypertrophy has usually been regarded as an adaptive response to hemodynamic load in postnatal hearts when cardiomyocytes irreversibly withdraw from cell cycle activity (3, 4). As a part of the normal developmental process, the cell cycle activity of cardiomyocyte declines rapidly upon terminal differentiation and maturation. At birth, the majority of cardiomyocytes (97%) stops proliferation and remains in G 0 /G 1 phase (5, 6). This cardiomyocyte cell cycle withdraw is considered a key phenomenon in the heart switching from hyperplastic growth to hypertrophic growth (3).Cardiac hypertrophy has traditionally been classified as pathological or physiological (7). For example, persistent pressure or volume overload caused by disease conditions, such as hypertension, stenotic cardiac valve disorders, and genetic defects in contractile proteins, can induce cardiac pathological hypertrophy, which can be associated with diminished heart function and eventual heart failure (8, 9). In contrast, physiological cardiac hypertrophy is a normal beneficial adaptive response of the heart to phys...

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