CDK1 inhibitors(Cyclin-dependent kinase 1 inhibitors), CDK2 inhibitors(Cyclin-dependent kinase 2 inhibitors), CDK4 inhibitors(Cyclin-dependent kinase 4 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Solid tumor

Originator Organization

Nerviano Medical Sciences S.r.l

Active Organization-

Inactive Organization

Nerviano Medical Sciences S.r.lNerviano Medical Sciences Group SRL

License Organization-

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC19H31N5O2

InChIKeyHUXYBQXJVXOMKX-UHFFFAOYSA-N

CAS Registry718630-59-2

Clinical Trials associated with PHA-793887

NCT00996255

/ TerminatedPhase 1

A Phase I Dose-Escalation Study of PHA-793887 Administered as a 1-hour IV Infusion on Days 1, 8 and 15 in a 4-Week Cycle in Patients With Advanced/Metastatic Solid Tumors

The purpose of this open-label, multi center, phase I study, was to determine the safety profile of PHA-793887 administered by intravenous infusion to patients with advanced/metastatic solid tumors. This was a dose-finding study to determine the maximum tolerated dose and the dose of PHA-793887 that can be safely used in phase II investigations.

Start Date01 Nov 2006

Sponsor / Collaborator

Nerviano Medical Sciences S.r.l

100 Clinical Results associated with PHA-793887

100 Translational Medicine associated with PHA-793887

100 Patents (Medical) associated with PHA-793887

Literatures (Medical) associated with PHA-793887

01 Dec 2024·Cellular and Molecular Life Sciences

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons

Article

Author: Zhen, Shannon ; Petrova, Veselina ; Splaine, Jennifer ; Snavely, Andrew R ; Pandey, Roshan ; Hermawan, Crystal ; Woolf, Clifford J ; Singh, Bhagat ; Barrett, Lee B ; Chen, Kuchuan ; Smith, Jennifer A ; Cheng, Anya

AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient’s quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

01 Dec 2024·Protein & Peptide Letters

SGSM2 in Uveal Melanoma: Implications for Survival, Immune Infiltration, and Drug Sensitivity

Article

Author: Pang, Yanhua ; Liang, Demao ; Yan, Rili ; Zhang, Qiuli ; Ke, Yi

Background:The abnormal expression of small G protein signaling modulator 2 (SGSM2) is related to the occurrence of thyroid cancer and breast cancer. However, the role of SGSM2 in uveal melanoma (UVM) is unclear.Objects:To elucidate this ambiguity, our study utilized bioinformatics analysis and experimental validation.Methods:The expression of SGSM2 was detected in UVM cell lines through quantitative real-- time PCR (qRT-PCR). We utilized the Cancer Genome Atlas (TCGA) database to assess the relationship between SGSM2 expression and clinical characteristics, as well as its prognostic significance in UVM. Furthermore, the study examined potential regulatory networks involving SGSM2 in relation to immune infiltration, immune checkpoint genes, microsatellite instability (MSI), and drug sensitivity in UVM. The study also examined SGSM2 expression in UVM single-cell sequencing data.Results:SGSM2 was highly expressed in UVM cell lines. Moreover, elevated levels of SGSM2 in UVM patients were significantly linked to poorer overall survival (OS) (p < 0.001), progress- free survival (PFS) (p < 0.001), and disease-specific survival (DSS) (p < 0.001). Additionally, SGSM2 expression was identified as an independent prognostic factor in UVM patients (p < 0.001). SGSM2 was associated with several pathways, including the calcium signaling pathway, natural killer cell-mediated cytotoxicity, cell adhesion molecules (CAMs), and others. The study revealed that SGSM2 expression in UVM is linked to immune infiltration, immune checkpoint genes, and MSI. Additionally, a significant inverse correlation was observed between SGSM2 expression and the compounds GSK690693, TL-2-105, PHA-793887, Tubastatin A, and SB52334 in UVM patients.Conclusion:SGSM2 may not only serve as an important indicator for prognostic assessment. Still, it may also be a key target for the development of new therapeutic approaches, providing new perspectives on the treatment of UVM patients.

04 Sep 2024·Biochemical Journal

Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation

Article

Author: Meng, Yanxiang ; Hildebrand, Joanne M. ; Young, Samuel N. ; Garnish, Sarah E. ; Murphy, James M. ; Horne, Christopher R. ; Jacobsen, Annette V.

Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, the MLKL (mixed lineage kinase domain-like) pseudokinase. Downstream of death and Toll-like receptor stimulation, MLKL is trafficked to the plasma membrane via the Golgi-, actin- and microtubule-machinery, where activated MLKL accumulates until a critical lytic threshold is exceeded and cell death ensues. Mechanistically, MLKL's lytic function relies on disengagement of the N-terminal membrane-permeabilising four-helix bundle domain from the central autoinhibitory brace helix: a process that can be experimentally mimicked by introducing the R30E MLKL mutation to induce stimulus-independent cell death. Here, we screened a library of 429 kinase inhibitors for their capacity to block R30E MLKL-mediated cell death, to identify co-effectors in the terminal steps of necroptotic signalling. We identified 13 compounds — ABT-578, AR-A014418, AZD1480, AZD5363, Idelalisib, Ipatasertib, LJI308, PHA-793887, Rapamycin, Ridaforolimus, SMI-4a, Temsirolimus and Tideglusib — each of which inhibits mammalian target of rapamycin (mTOR) signalling or regulators thereof, and blocked constitutive cell death executed by R30E MLKL. Our study implicates mTOR signalling as an auxiliary factor in promoting the transport of activated MLKL oligomers to the plasma membrane, where they accumulate into hotspots that permeabilise the lipid bilayer to cause cell death.

100 Deals associated with PHA-793887

External Link

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	Italy	Nerviano Medical Sciences Group SRL	-
Solid tumor	Phase 1	Italy	Nerviano Medical Sciences Group SRL	-

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