Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK)

Lam, Betty; Arikawa, Yasuyoshi; Cramlett, Joshua; Dong, Qing; Jong, Ron de; Feher, Victoria A.; Grimshaw, Charles E.; Farrell, Pamela; Hoffman, Isaac; Jennings, Andy; Jones, Benjamin; Matuszkiewicz, Jennifer; Miura, Joanne; Miyake, Hiroshi; Natala, Srinivasa Reddy; Shi, Lihong; Takahashi, Masashi; Taylor, Ewan R.; Wyrick, Corey; Yano, Jason; Zalevsky, Jonathan; Nie, Zhe

doi:10.1016/j.bmcl.2016.10.087

Cited by 57 publications

(44 citation statements)

References 25 publications

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“…The estimated sample sizes for the DLBCL and iNHL expansion cohorts were based on a Simon 2-stage design using the following parameters: a 1-sided test at the significance level of =0.1, a power of 80%, a null hypothesis of an ORR of ≤20% for DLBCL and ≤35% for iNHL, and an alternative hypothesis of an ORR of ≥40% for DLBCL and ≥60% for iNHL. A total of 12-25 DLBCL patients (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) patients projected based on a 15% dropout rate) and 10-23 iNHL patients (14-27 patients projected based on a 15% dropout rate) would be needed for the expansion cohorts.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, evidence suggests the SYK pathway may also be implicated in select solid tumors (12)(13)(14)(15). TAK-659 is an investigational, oral, reversible, and potent dual inhibitor of SYK and FMS-like tyrosine kinase 3 (FLT3) (16). TAK-659 has demonstrated inhibitory activity in preclinical models of diffuse large B-cell lymphoma (DLBCL), in a RL follicular lymphoma (FL) cell line (17), and in chronic lymphocytic leukemia (CLL) cells (18).…”

Section: Introductionmentioning

confidence: 99%

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Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma

Kaplan

Popat

et al. 2020

Clinical Cancer Research

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are employed by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. S. Wang has ownership interests in Takeda Pharmaceutical Company Limited. K. Stumpo has equity ownership in Astra Zeneca and Teva, and has family members with stock ownership in Bristol-Myers Squibb, AstraZeneca, GSK. I. Proscurshim is a former employee of Agenus. F. Bosch declares consultancy for, and has received honoraria and paid expert testimony from Roche, Novartis, Janssen, AbbVie, Gilead, and Mundipharma, and has

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma

Kaplan

Popat

et al. 2020

Clinical Cancer Research

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“…Finally, several studies have shown the importance of BTK in FLT3 AML pathogenesis [32,33]. Together, these studies suggest that the use of a multi-kinase inhibitor targeting SFK and BTK could achieve clinical benefit by targeting upstream regulators of FLT3 similar to the use of dual FLT3/SYK inhibitors in AML [31,34,35].…”

Section: Introductionmentioning

confidence: 92%

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

et al. 2020

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Background: Acute myeloid leukemia (AML) is the most common type of adult leukemia. Several studies have demonstrated that oncogenesis in AML is enhanced by kinase signaling pathways such as Src family kinases (SFK) including Src and Lyn, spleen tyrosine kinase (SYK), and bruton's tyrosine kinase (BTK). Recently, the multi-kinase inhibitor ArQule 531 (ARQ 531) has demonstrated potent inhibition of SFK and BTK that translated to improved preclinical in vivo activity as compared with the irreversible BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) models. Given the superior activity of ARQ 531 in CLL, and recognition that this molecule has a broad kinase inhibition profile, we pursued its application in pre-clinical models of AML. Methods: The potency of ARQ 531 was examined in vitro using FLT3 wild type and mutated (ITD) AML cell lines and primary samples. The modulation of pro-survival kinases following ARQ 531 treatment was determined using AML cell lines. The effect of SYK expression on ARQ 531 potency was evaluated using a SYK overexpressing cell line (Ba/F3 murine cells) constitutively expressing FLT3-ITD. Finally, the in vivo activity of ARQ 531 was evaluated using MOLM-13 disseminated xenograft model. Results: Our data demonstrate that ARQ 531 treatment has anti-proliferative activity in vitro and impairs colony formation in AML cell lines and primary AML cells independent of the presence of a FLT3 ITD mutation. We demonstrate decreased phosphorylation of oncogenic kinases targeted by ARQ 531, including SFK (Tyr416), BTK, and fms-related tyrosine kinase 3 (FLT3), ultimately leading to changes in downstream targets including SYK, STAT5a, and ERK1/2. Based upon in vitro drug synergy data, we examined ARQ 531 in the MOLM-13 AML xenograft model alone and in combination with venetoclax. Despite ARQ 531 having a less favorable pharmacokinetics profile in rodents, we demonstrate modest single agent in vivo activity and synergy with venetoclax. Conclusions: Our data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.

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“…Our earlier studies also demonstrated that the novel BTK inhibitor Abivertinib is effective in inhibiting MCL survival (4). Efficacy of BTK inhibition as a single agent therapy is powerful, but resistance may develop, fueling the development of combination therapies that improve clinical responses (5)(6)(7)(8)(9)(10)(11)(12)(13). Recent studies have investigated the combination of BTK inhibitor PLS-123 and the mammalian target of rapamycin (mTOR) inhibitor everolimus synergy to attenuate proliferation and motility of MCL cell lines (13).…”

Section: Ivyspringmentioning

confidence: 99%

Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro

Huang¹,

Yu²,

Shi³

et al. 2020

J. Cancer

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Background: Apigenin, a flavonoid phytochemical extracted from fruits and vegetables, has shown anti-neoplastic effects in a variety of malignant tumors. DLBCL is the most common type of aggressive lymphoma in adults with a poor prognosis. Small-molecule inhibitors like BTK inhibitors have demonstrated extended period of disease control. Whereas the effects of the synergetic inhibition of the two have not been elucidated. Methods: We assessed the efficacy of Apigenin alone or combined with Abivertinib to inhibit DLBCL progression. Cell viability was examined using the cell proliferation cell proliferation assay (MTS). Apoptotic cells and cell cycle evaluation were detected by Annexin V-FITC and DNA staining solution respectively. Western blot was used to explore the potential mechanism, and the in vivo effects of the two drugs were performed by a DLBCL xenograft BALB/c nude mice model. Results: Our results demonstrated that Apigenin can inhibit the proliferation and clone forming of DLBCL cells. Apigenin also induces apoptosis by down-regulating BCL-XL and activating Caspase family. In addition, Apigenin down-regulates cell cycle proteins including CDK2/CDK4/CDK6/CDC2/p-RB to increase G2/M phase arrest. Mechanically, our data demonstrate that Apigenin leads to a significant reduction of the expression of pro-proliferative pathway PI3K/mTOR to inhibit DLBCL cells survival. Moreover, our in vitro and in vivo results show that Apigenin can synergize with Abivertinib, a novel BTK inhibitor, in treating DLBCL visa synergistically inducing apoptosis and inhibiting the p-GS3K-β and its downstream targets. Conclusions: Collectively, our study suggests that Apigenin exerts improving anti-lymphoma effect of BTK inhibitors and provides hope to targeted therapy of those develop resistance.

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Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK)

Cited by 57 publications

References 25 publications

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

Apigenin and Abivertinib, a novel BTK inhibitor synergize to inhibit diffuse large B-cell lymphoma in vivo and vitro

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