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    • Considering its role in regulating cytoskeletal

    2022-05-13

    Considering its role in regulating cytoskeletal dynamics, the Rho kinase effector ROCK has been particularly implicated in tumor metastasis. The ROCK inhibitors Y27632 and fasudil have been extensively studied in cancer and beneficial effects have been observed in many types of cancers (Kale et al., 2015, Rath and Olson, 2012). This supports the development of selective ROCK inhibitors for cancer therapy. Several recently developed ROCK inhibitors have been proven to be more potent and/or selective compared to Y27632 or fasudil. For example, OXA-06 and PT262 inhibit migration and invasion of NSCLC Colistin Methanesulfonate sodium salt (Tsai et al., 2011, Vigil et al., 2012), RKI-1447 inhibits breast cancer cell invasion (Patel et al., 2012, Patel et al., 2014), and CCT129253 and AT13148 impaired melanoma cell invasion and metastasis in vivo (Sadok et al., 2015). However, targeting ROCK also comes with the liability of playing an important role in the contraction of blood vessels. As such, ROCK inhibitors have a high likelihood of inducing hypotension (Kale et al., 2015). Further, inhibition of ROCK can also increase survival of cancer stem cells (Castro et al., 2013, Ohata et al., 2012). Importantly, and rather counterintuitive, there are also reports of ROCK inhibition resulting in increased pro-invasive behavior (Bhandary et al., 2015, Zhang et al., 2011). As such, despite the significant promise ROCK inhibitors exhibited in experimental studies, no clinical trials on ROCK inhibition in solid tumors have been completed to date although a phase 1 trial on AT13148 was initiated in 2012 (NCT01585701) and is expected to complete in 2017. For a more extensive overview of ROCK inhibitors we refer to (Loirand, 2015). Inhibition of Rac signaling has provided promising in vitro results. The Rac inhibitor NSC23766 effectively inhibits Rac1 activation by blocking a surface groove that is critical for the interaction with the Rac GEFs Tiam1 and Trio (Gao, Dickerson, Guo, Zheng, & Zheng, 2004). In lymphomas, NSC23766 blocks dissemination in xenograft studies (Thomas et al., 2007). However, the potency of NSC23766 is insufficient to be considered for clinical application. Other, more potent, inhibitors have been developed using NSC23766 as a starting point, such as EHop-016, which blocks the interaction between the GEF Vav2 and Rac1 (Montalvo-Ortiz et al., 2012). In addition, non-competitive inhibitors have been developed, such as EHT 1864 (Shutes et al., 2007). Both EHop-016 and EHT 1864 decrease decreases migration of metastatic breast cancer cells (Katz et al., 2012, Montalvo-Ortiz et al., 2012). Several novel compounds that target both activation of Rac1 and Cdc42 have been developed in recent years, using the structure of NSC23766 as a starting point. For example, AZA1 inhibits cellular migration of prostate cancer cells in xenograft models via inhibition of Rac1 and Cdc42 but not RhoA GTPase activity (Zins, Lucas, Reichl, Abraham, & Aharinejad, 2013), while a Cdc42-selective small-molecule inhibitor, AZA197, suppresses colorectal carcinoma cell migration (Zins et al., 2013, Zins et al., 2013). Other small molecule modulators targeting Cdc42 interaction with the GEF intersectin have also been developed such as Casin (Florian et al., 2012) and ZCL278, which supresses actin-based motility and migration in prostate cancer (Friesland et al., 2013). Recently, ML141 was identified as a noncompetitive allosteric inhibitor with excellent selectivity towards Cdc42 (Hong et al., 2013) and was shown to interfere with collective migration downstream of P-cadherin/β-Pix (Plutoni et al., 2016). Downstream of Rac and Cdc42, PAKs are increasingly recognized as plausible therapeutical targets. To date, several PAK inhibitors have been developed. The non-competitive inhibitor IPA-3 was designed to target PAKs independent of ATP by adding a sulfhydryl moiety to the N-terminal region, thereby promoting the inhibitory conformation (Deacon et al., 2008). IPA-3 reduces tumor progression in hepatocellular carcinoma and prostate cancer xenograft models (Al-Azayzih et al., 2016, Wong et al., 2013). However, the downside of promoting the inhibitory conformation of PAKs is that IPA-3 is ineffective in inhibiting pre-activated PAK. Thus, the use IPA-3 against cancer cells with elevated PAK activity may not be effective. In addition, the continuous reduction of the sulfhydryl moiety makes IPA-3 unsuitable for further clinical development. Recently, new 1,4-naphthohydroquinone-based compounds have been identified that allosterically interact with PAKs but do not induce the formation of covalent modifications (Kim et al., 2016). The only ATP-competitive PAK inhibitor that has progressed to a clinical trial is PF-3758309 (Murray et al., 2010). Although it remain difficult to ascribe the effects solely to PAK inhibition due to its poor target selectivity, the compound showed promising results and in vitro and in vivo studies in preclinical cancer models (Bradshaw-Pierce et al., 2013, Chow et al., 2012, Murray et al., 2010, Pitts et al., 2013), however, due to undesirable pharmacokinetics, the lack of a dose-response relationship, and adverse effects, the trial was prematurely terminated. More recently, the pyridopyrimidinone FRAX597 was identified by high-throughput screening as a potent inhibitor of PAKs and displays potent anti-tumor activity in vitro and in vivo (Chow et al., 2012, Chow et al., 2015, Licciulli et al., 2013, Mortazavi et al., 2015, Yeo et al., 2016). Other compunds identified in these screens, FRAX486 and FRAX1036, similarly exhibit excellent PAK1 potency, however all of these compound demonstrated poor permeability and adverse inhibition of hERG potassium channels. Adressing these issues, the G-5555 compound was developed based on the structure of FRAX1036 (Ndubaku et al., 2015). While the compound shows desirable in vivo pharmacokinetics and demonstrated excellent in vitro growth inhibition in cancer cell lines, a xenograft study revealed that G-5555 was associated with accute cardiovascular toxicity (Rudolph et al., 2016), suggesting that G-5555, is not suitable for further clinical development. Several other ATP-competitive PAK1 inhibiting compounds have recently been disclosed (McCoull et al., 2016), but have until now not been studied as anticancer agents.