The Use of Virtual Screening in ALK5 Kinase Inhibitor Discovery and Validation of Orally Active ALK5 Kinase Inhibitors in Oncology

Ling, Leona; Singh, Juswinder; Chuaqui, Claudio; Boriack-Sjodin, P.A.; Corbley, Michael J.; LePage, Doreen; Silverio, Erika L.; Sun, Lihong; Papadatos, James L.; Shan, Feng; Pontz, Timothy; Cheung, Hung Kam; Zhang, Xiamei; Arduini, Robert M.; Mead, Jonathan N.; Newman, Miki; Bowes, Scott; Josiah, Serene; Lee, Wen‐Cherng

doi:10.1007/978-1-59745-293-9_41

Cited by 5 publications

(7 citation statements)

References 31 publications

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“…SM16, an ALK5/ALK4 kinase inhibitor with a molecular weight of 430, was described previously (13). 3 Briefly, SM16 binds ALK5 (K i , 10 nmol/L) and ALK4 (K i , 1.5 nmol/L) with high affinity at the ATP-binding site.…”

Section: Alk5 Inhibitor (Sm16)mentioning

confidence: 99%

“…Many human cancers show a correlation between overexpression of TGFh and advanced disease or poor prognosis (1)(2)(3). Neutralization of TGFh has shown potential clinical utility in a variety of murine models of cancer, including breast cancer (4)(5)(6)(7)(8), thymoma (9), hepatocellular carcinoma (10), glioma (11,12), head and neck carcinoma (13), and malignant mesothelioma (14,15). Depending on the model, the antitumor activity of TGFh antagonists is mediated by one or more autocrine or paracrine mechanisms, including increased immune surveillance, inhibition of angiogenesis, inhibition of invasion, metastases and epithelial to mesenchymal transition, as well as the inhibition of collagen deposition and tumor interstitial pressure (1,2,(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

“…Several of these ALK5 kinase inhibitors have shown efficacy in models of fibrosis (23)(24)(25). 3 However, the efficacy of ALK5 inhibitors in preventing tumor growth was only recently shown in an orthotopic model of glioma (12), and several recent reports suggest activity in breast, head and neck, and lung cancer tumor models (13,26,27).…”

Section: Introductionmentioning

confidence: 99%

“…To determine if ALK5 kinase inhibitors are effective in treating malignant mesothelioma, we used a novel ALK5 inhibitor, SM16 (13). 3 This small-molecule kinase inhibitor, like those previously described (28), was shown to be a potent selective inhibitor of ALK5 and ALK4, the activin type IB receptor.…”

Section: Introductionmentioning

confidence: 99%

“…Although this article focused in detail on a mesothelioma cell line, we have data that SM16 has similar antitumor effects in other types of established tumors, including pharyngeal carcinoma (13), colorectal carcinoma, lung cancer, and thymoma (Supplementary Data).…”

mentioning

confidence: 99%

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A Novel Small-Molecule Inhibitor of Transforming Growth Factor β Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection

et al. 2007

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Malignant mesothelioma is an aggressive and lethal pleural cancer that overexpresses transforming growth factor B (TGFB). We investigated the efficacy of a novel small-molecule TGFB type I receptor (ALK5) kinase inhibitor, SM16, in the AB12 syngeneic model of malignant mesothelioma. SM16 inhibited TGFB signaling seen as decreased phosphorylated Smad2/3 levels in cultured AB12 cells (IC 50 , f200 nmol/L). SM16 penetrated tumor cells in vivo, suppressing tumor phosphorylated Smad2/3 levels for at least 3 h following treatment of tumor-bearing mice with a single i.p. bolus of 20 mg/kg SM16. The growth of established AB12 tumors was significantly inhibited by 5 mg/kg/d SM16 (P < 0.001) delivered via s.c. miniosmotic pumps over 28 days. The efficacy of SM16 was a result of a CD8 + antitumor response because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice and (b) CD8 + T cells isolated from spleens of mice treated with SM16 showed strong antitumor cytolytic effects whereas CD8 + T cells isolated from spleens of tumor-bearing mice treated with control vehicle showed minimal activity. Treatment of mice bearing large tumors with 5 mg/kg/d SM16 after debulking surgery reduced the extent of tumor recurrence from 80% to <20% (P < 0.05). SM16 was also highly effective in blocking and regressing tumors when given p.o. at doses of 0.45 or 0.65 g/kg in mouse chow. Thus, SM16 shows potent activity against established AB12 malignant mesothelioma tumors using an immune-mediated mechanism and can significantly prevent tumor recurrence after resection of bulky AB12 malignant mesothelioma tumors. These data suggest that ALK5 inhibitors, such as SM16, offer significant potential for the treatment of malignant mesothelioma and possibly other cancers.

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Section: Alk5 Inhibitor (Sm16)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel Small-Molecule Inhibitor of Transforming Growth Factor β Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection

et al. 2007

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Pareto optimization to accelerate multi-objective virtual screening

Fromer,

Graff,

Coley

2024

Digital Discovery

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The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling

et al. 2017

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KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.

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The Use of Virtual Screening in ALK5 Kinase Inhibitor Discovery and Validation of Orally Active ALK5 Kinase Inhibitors in Oncology

Cited by 5 publications

References 31 publications

A Novel Small-Molecule Inhibitor of Transforming Growth Factor β Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection

A Novel Small-Molecule Inhibitor of Transforming Growth Factor β Type I Receptor Kinase (SM16) Inhibits Murine Mesothelioma Tumor Growth In vivo and Prevents Tumor Recurrence after Surgical Resection

Pareto optimization to accelerate multi-objective virtual screening

The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling

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