Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility

Ohashi, Taiki; Oguro, Yuya; Tanaka, Toshio; Shiokawa, Zenyu; Tanaka, Yuta; Shibata, Sachio; Sato, Yoshihiko; Yamakawa, Hiroko; Hattori, Harumi; Yamamoto, Yoshiyuki; Kondo, Shigeru; Miyamoto, Maki; Nishihara, Masateru; Ishimura, Yoshimasa; Tojo, Hideaki; Baba, Atsuo; Sasaki, Satoshi

doi:10.1016/j.bmc.2012.07.034

Cited by 64 publications

(44 citation statements)

References 6 publications

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“…In preclinical studies, the compound showed a 50% inhibitory concentration (IC 50 ) of Gli1 transcriptional activity of 4.4 nmol/L (15). TAK-441 is highly specific; assayed against a panel of 126 enzymes and transporters, 10 mmol/L TAK-441 demonstrated >50% inhibition of only the human phosphodiesterase type 4 inhibitor (PDE4) and the human dopamine transporter (Takeda Pharmaceuticals International Co., data on file).…”

Section: Introductionmentioning

confidence: 99%

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Goldman¹,

Eckhardt

Borad

et al. 2015

Clinical Cancer Research

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Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway.Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50-1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/ feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1.Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade !3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n ¼ 4) and fatigue (n ¼ 3) were most common. Oral absorption was fairly rapid; median T max was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentrationtime curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors).Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling.

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Section: Introductionmentioning

confidence: 99%

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Goldman¹,

Eckhardt

Borad

et al. 2015

Clinical Cancer Research

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“…piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide) is a potent, selective hedgehog signaling pathway inhibitor that binds to smoothened (Smo) and is being developed for the treatment of cancer (Ohashi et al, 2012). It is well known that the hedgehog pathway regulates cell proliferation (Ingham and McMahon, 2001).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of Hedgehog Inhibitor TAK-441 for the Inhibition of Gli1 messenger RNA Expression and Antitumor Efficacy in Xenografted Tumor Model Mice

et al. 2013

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6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo [3,2-c]pyridine-2-carboxamide (TAK-441) is a potent, selective hedgehog signaling pathway inhibitor that binds to Smo and is being developed for the treatment of cancer. The objectives of these studies were to explore the possibility of establishing of a link between the pharmacokinetics of TAK-441 and the responses of Gli1 mRNA in tumor-associated stromal or skin cells and the antitumor effect of hedgehog inhibition. To this end, we built pharmacokinetic and pharmacodynamic models that describe the relationship of the concentrations of TAK-441 plasma to the responses of Gli1 mRNA in the tumor (target) and skin (surrogate) and to tumor growth inhibition in mice bearing xenografts of human pancreatic tumors (PAN-04). The responses of Gli1 mRNA and tumor growth were described by an indirect response model and an exponential tumor growth model, respectively. The IC 50 values for Gli1 mRNA inhibition in the tumor and skin by TAK-441 were estimated to be 0.0457 and 0.113 mg/ml, respectively. The IC 90 value for tumor growth inhibition was estimated to be 0.68 mg/ml. These results suggest that a >83% inhibition of Gli1 mRNA expression in the skin or a >94% inhibition of Gli1 mRNA expression in the tumor would be required to sufficiently inhibit (>90%) hedgehog-related tumor growth in the xenografted model mice. We conclude that Gli1 mRNA expression in the tumor and skin could be a useful biomarker for predicting the antitumor effect of hedgehog inhibitors

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“…In our previous report, the lack of carbonyl group in the side chain or benzene ring resulted in decrease of activity. 8 Considering our previous knowledge and necessity of regulation, the benzamide moiety would be a proper substituent at 5-position.…”

Section: Resultsmentioning

confidence: 99%

“…1). 7,8 However, it was still unclear that exact role of the core skeleton including substituents at the 4-and 5-positions. Thus, we evaluated the modification of central core to confirm these properties and discovered new potent Hh signaling inhibitors with novel skeletons compared to that of 1.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and evaluation of hedgehog signaling inhibitor with novel core system

Ohashi

Tanaka

Shiokawa

et al. 2015

Bioorganic & Medicinal Chemistry

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Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility

Cited by 64 publications

References 6 publications

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Pharmacokinetic and Pharmacodynamic Modeling of Hedgehog Inhibitor TAK-441 for the Inhibition of Gli1 messenger RNA Expression and Antitumor Efficacy in Xenografted Tumor Model Mice

Synthesis and evaluation of hedgehog signaling inhibitor with novel core system

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