An Open-label, Phase I Study to determine the Safety and Pharmacokinetics of JNJ-26483327, a Multi-targeted Kinase Inhibitor, administered to Subjects with Advanced Stage and/or Refractory Solid Malignancies - Dose escalation safety and Pharmacokinetic study.

Start Date26 Oct 2006

Sponsor / Collaborator-

NCT00676299 / CompletedPhase 1

An Open-label, Phase I Study to Determine the Safety and Pharmacokinetics of JNJ-26483327, a Multi-targeted Kinase Inhibitor, Administered to Subjects With Advanced Stage and/or Refractory Solid Malignancies

The purpose of this study is to assess JNJ-26483327 (a drug in development for cancer) for the safety of the drug in patients with advanced solid tumors that have not responded or are no longer responding to available therapies. The absorption, breakdown and elimination of the drug will also be studied.

Start Date01 Aug 2006

Sponsor / Collaborator

Johnson & Johnson Pharmaceutical Research & Development LLC

[+1]

100 Clinical Results associated with FLT3 x SRC

100 Translational Medicine associated with FLT3 x SRC

0 Patents (Medical) associated with FLT3 x SRC

Literatures (Medical) associated with FLT3 x SRC

01 Sep 2022·European Journal of Medicinal Chemistry

Dual-target Janus kinase (JAK) inhibitors: Comprehensive review on the JAK-based strategies for treating solid or hematological malignancies and immune-related diseases

Review

Author: Wang, Yezhi ; Qin, Lian ; Jia, Xiangxiang ; Shen, Pei ; Li, Zhiyu ; Feng, Xi ; Qiu, Zhixia ; Xu, Pengfei

Janus kinases (JAKs) are the non-receptor tyrosine kinases covering JAK1, JAK2, JAK3, and TYK2 which regulate signal transductions of hematopoietic cytokines and growth factors to play essential roles in cell growth, survival, and development. Dysregulated JAK activity leading to a constitutively activated signal transducers and activators of transcription (STAT) is strongly associated with immune-related diseases and cancers. Targeting JAK to interfere the signaling of JAK/STAT pathway has achieved quite success in the treatment of these diseases. However, inadequate clinical response and serious adverse events come along by the treatment of monotherapy of JAK inhibitors. With better and deeper understanding of JAK/STAT pathway in the pathogenesis of diseases, researchers start to show huge interest in combining inhibition of JAK and other oncogenic targets to realize a broader regulation on pathological processes to block disease development and progression, which has hastened extensive research of dual JAK inhibitors over the past decades. Until now, studies of dual JAK inhibitors have added BTK, SYK, FLT3, HDAC, Src, and Aurora kinases to the overall inhibitory profile and demonstrated significant advantage and superiority over single-target inhibitors. In this review, we elucidated the possible mechanism of synergic effects caused by dual JAK inhibitors and briefly describe the development of these agents.

01 Dec 2020·Journal of Hematology & OncologyQ1 · MEDICINE

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

Q1 · MEDICINE

ArticleOA

Author: Mitchell, Shaneice ; Truxall, Jean ; Eathiraj, Sudharshan ; Elgamal, Ola A ; Schwartz, Brian ; Lehman, Amy ; Goettl, Virginia M ; Lapalombella, Rosa ; Tran, Minh ; Stegmaier, Kimberly ; Carmichael, Bridget ; Baker, Sharyn D ; Jeon, Jae Yoon ; Wasmuth, Ronni ; Byrd, John C ; Orwick, Shelley J ; Mehmood, Abeera ; Hertlein, Erin

AbstractBackgroundAcute 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 pre-clinical 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.MethodsThe 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.ResultsOur 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 down-stream 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.ConclusionsOur data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.

01 Jul 2020·Histology and histopathologyQ4 · BIOLOGY

Next generation sequencing identifies novel potential actionable mutations for grade I meningioma treatment.

Q4 · BIOLOGY

Article

Author: Malapelle, Umberto ; Pisapia, Pasquale ; Conticelli, Floriana ; Troncone, Giancarlo ; Martinez, Juan Carlos ; Pepe, Francesco ; Del Basso de Caro, Maria Laura

Meningiomas are common brain tumors that arise from the meningeal membranes that envelope the brain and spinal cord. The World Health Organization classifies these tumors into three histopathological grades. Because of tumor recurrence, treating meningiomas may be challenging even in well-differentiated grade I (GI) neoplasms. Indeed, around 5% of completely resected GI meningiomas relapse within 5 years. Therefore, identifying driver mutations in GI meningiomas through next generation sequencing (NGS) assays is paramount. The aim of this study was to validate the use of the 50-gene AmpliSeq Hotspot Cancer Panel v2 to identify the mutational status of 23 GI meningioma, namely, 12 non recurrent and 11 recurrent. In 18 out of the 23 GI meningiomas analyzed, we identified at least one gene mutation (78.2%). The most frequently mutated genes were c-kit (39.1%), ATM (26.1%), TP53 (26.1%), EGFR (26.1%), STK11 (21.7%), NRAS (17.4%), SMAD4 (13%), FGFR3 (13%), and PTPN11 (13%); less frequent mutations were SMARCB1 (8.7%), FLT3 (8.7%), KRAS (8.7%), FBWX7 (8.7%), ABL1 (8.7%), ERBB2 (8.7%), IDH1 (8.7%), BRAF (8.7%), MET (8.7%), HRAS (4.3%), RB1 (4.3%), CTNNB1 (4.3%), PIK3CA (4.3%), VHL (4.3%), KDR (4.3%), APC (4.3%), NOTCH1 (4.3%), JAK3 (4.3%), and SRC (4.3%). To our knowledge, mutations in all of these genes, except for TP53, STK11, SMARCB1, PIK3CA, VHL, and BRAF, have never been described before in meningiomas. Hence, these findings demonstrate the viability of NGS to detect new genetic alterations in GI meningiomas. Equally important, this technology enabled us to detect possible novel actionable mutations not previously associated with GI and for which selective inhibitors already exist.

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