KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma

Ciesielski, Michael; Bu, Yahao; Munich, Stephan A; Teegarden, Paola; Smolinski, Michael; Clements, James L.; Lau, Johnson Y. N.; Hangauer, David; Fenstermaker, Robert A.

doi:10.1007/s11060-018-2992-4

Cited by 10 publications

(5 citation statements)

References 38 publications

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“…KX2-361 was investigated against human and murine glioma cells and also in a syngeneic orthotopic GBM murine model [146]. Interestingly, it reduced Src autophosphorylation, and disrupted microtubule structure in the GL261 murine GBM cell line.…”

Section: Kx2-361mentioning

confidence: 99%

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

Frumento,

Grossi,

Falesiedi

et al. 2024

IJMS

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In the last decade, many small molecules, usually characterized by heterocyclic scaffolds, have been designed and synthesized as tyrosine kinase inhibitors (TKIs). Among them, several compounds have been tested at preclinical and clinical levels to treat glioblastoma multiforme (GBM). GBM is the most common and aggressive type of cancer originating in the brain and has an unfavorable prognosis, with a median survival of 15–16 months and a 5-year survival rate of 5%. Despite recent advances in treating GBM, it represents an incurable disease associated with treatment resistance and high recurrence rates. For these reasons, there is an urgent need for the development of new pharmacological agents to fight this malignancy. In this review, we reported the compounds published in the last five years, which showed promising activity in GBM preclinical models acting as TKIs. We grouped the compounds based on the targeted kinase: first, we reported receptor TKIs and then, cytoplasmic and peculiar kinase inhibitors. For each small molecule, we included the chemical structure, and we schematized the interaction with the target for some representative compounds with the aim of elucidating the mechanism of action. Finally, we cited the most relevant clinical trials.

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Section: Kx2-361mentioning

confidence: 99%

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

Frumento,

Grossi,

Falesiedi

et al. 2024

IJMS

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“…Preclinical in vivo results indicated that KX2-391 significantly inhibited the primary tumor growth in various animal models. Moreover, KX2-391 showed stronger tumor metastasis inhibition than paclitaxel, which may be attributed to its Src inhibitory activity. − Similarly, KX2-361 induced 30% long-term complete tumor remission in the animal model, and it has good oral bioavailability (40%) and superior BBB penetration in mice. , Currently, KX2-391 is undergoing phase III clinical trials for the treatment of actinic keratosis with good efficacy and low toxicity (NCT03285477). And KX2-361 is undergoing phase I clinical trials for the treatment of malignant glioblastoma (NCT02326441).…”

Section: Dual Inhibitors Of Tubulin and Other Tumor-related Targetsmentioning

confidence: 99%

“…130−133 Similarly, KX2-361 induced 30% long-term complete tumor remission in the animal model, and it has good oral bioavailability (40%) and superior BBB penetration in mice. 126,134 Currently, KX2-391 is undergoing phase III clinical trials for the treatment of actinic keratosis with good efficacy and low toxicity (NCT03285477). And KX2-361 is undergoing phase I clinical trials for the treatment of malignant glioblastoma (NCT02326441).…”

Section: Dual Inhibitors Of Tubulin and Othermentioning

confidence: 99%

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy

et al. 2021

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Microtubules play a crucial role in multiple cellular functions including mitosis, cell signaling, and organelle trafficking, which makes the microtubule an important target for cancer therapy. Despite the great successes of microtubule-targeting agents in the clinic, the development of drug resistance and dose-limiting toxicity restrict their clinical efficacy. In recent years, multitarget therapy has been considered an effective strategy to achieve higher therapeutic efficacy, in particular dual-target drugs. In terms of the synergetic effect of tubulin and other antitumor agents such as receptor tyrosine kinases inhibitors, histone deacetylases inhibitors, DNA-damaging agents, and topoisomerase inhibitors in combination therapy, designing dual-target tubulin inhibitors is regarded as a promising approach to overcome these limitations and improve therapeutic efficacy. In this Perspective, we discussed rational target combinations, design strategies, structure−activity relationships, and future directions of dual-target tubulin inhibitors.

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“…Although clinical trials with this compound are still missing, it has been clearly demonstrated that KX2-361 had good oral bioavailability and that it easily crossed the BBB, reached the tumor site, and delayed tumor progression, therefore, enhancing long-term survival in mice. Interestingly, KX2-361 had no effect in immunocompromised mice indicating that its efficacy relied also on the host immune system [ 125 ].…”

Section: Targeting Src In Glioblastomamentioning

confidence: 99%

SRC Kinase in Glioblastoma: News from an Old Acquaintance

Cirotti

Contadini

Barilá

2020

Cancers

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Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.

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KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma

Cited by 10 publications

References 38 publications

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy

SRC Kinase in Glioblastoma: News from an Old Acquaintance

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