PKMYT1 inhibitors(protein kinase, membrane associated tyrosine/threonine 1 inhibitors), SRC inhibitors(Tyrosine-protein kinase SRC inhibitors), WEE1 inhibitors(Serine/threonine-protein kinase WEE1 inhibitors)

Therapeutic Areas

NeoplasmsCardiovascular Diseases

Active Indication

AtherosclerosisCoronary RestenosisNeoplasms+ [1]

Inactive Indication

Vascular restenosis

Originator Organization

Pfizer Inc.

Active Organization

Parke-Davis & Co. Ltd.

Sun Yat-Sen University

Inactive Organization

Pfizer Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with PD-0166285

100 Translational Medicine associated with PD-0166285

100 Patents (Medical) associated with PD-0166285

Literatures (Medical) associated with PD-0166285

07 Oct 2023·Medical oncology (Northwood, London, England)

HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285.

Article

Author: Shao, Xin ; Zhou, Ziwei ; Chu, Xuan ; Wan, Peng ; Zhang, Zhonghui ; Dan, Wenran ; Chen, Shuyu ; Liu, Beizhong ; Zhong, Liang ; Lu, Yang

Cytarabine-resistant acute myeloid leukemia (AML) is a common phenomenon, necessitating the search for new chemotherapeutics. WEE1 participates in cell cycle checkpoint signaling and inhibitors targeting WEE1 (WEE1i) constitute a potential novel strategy for AML treatment. HDAC (histone deacetylase) inhibitors have been shown to enhance the anti-tumor effects of WEE1i but molecular mechanisms of HDAC remain poorly characterized. In this study, the WEE1 inhibitor PD0166285 showed a relatively good anti-leukemia effect. Notably, PD0166285 can arise the expression of HDAC11 which was negatively correlated with survival of AML patients. Moreover, HDAC11 can reduced the anti-tumor effect of PD0166285 through an effect on p53 stability and the changes in phosphorylation levels of MAPK pathways. Overall, the cell cycle inhibitor, PD0166285, is a potential chemotherapeutic drug for AML. These fundings contribute to a functional understanding of HDAC11 in AML.

01 Jul 2020·Cell ReportsQ1 · BIOLOGY

The Apparent Requirement for Protein Synthesis during G2 Phase Is due to Checkpoint Activation

Q1 · BIOLOGY

ArticleOA

Author: Kamenz, Julia ; Lockhead, Sarah ; Reddy, Anay R ; Moskaleva, Alisa ; Chen, Yuxin ; Kang, Minjung ; Ferrell, James E ; Santos, Silvia D M

Protein synthesis inhibitors (e.g., cycloheximide) block mitotic entry, suggesting that cell cycle progression requires protein synthesis until right before mitosis. However, cycloheximide is also known to activate p38 mitogen-activated protein kinase (MAPK), which can delay mitotic entry through a G2/M checkpoint. Here, we ask whether checkpoint activation or a requirement for protein synthesis is responsible for the cycloheximide effect. We find that p38 inhibitors prevent cycloheximide-treated cells from arresting in G2 phase and that G2 duration is normal in approximately half of these cells. The Wee1 inhibitor MK-1775 and Wee1/Myt1 inhibitor PD0166285 also prevent cycloheximide from blocking mitotic entry, raising the possibility that Wee1 and/or Myt1 mediate the cycloheximide-induced G2 arrest. Thus, protein synthesis during G2 phase is not required for mitotic entry, at least when the p38 checkpoint pathway is abrogated. However, M phase progression is delayed in cycloheximide-plus-kinase-inhibitor-treated cells, emphasizing the different requirements of protein synthesis for timely entry and completion of mitosis.

01 May 2020·LeukemiaQ1 · MEDICINE

The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest

Q1 · MEDICINE

Article

Author: Bonnefoy, Nathalie ; Coopman, Peter ; Pouget, Jean-Pierre ; Karam, Jihad ; Constanzo, Julie ; Courteau, Alan ; Patzke, Sebastian ; Jarlier, Marta ; Navarro-Teulon, Isabelle ; Bardiès, Manuel ; Dahle, Jostein ; Repetto-Llamazares, Ada ; Marcatili, Sara ; Ladjohounlou, Riad ; Stenberg, Vilde ; Heyerdahl, Helen ; Cartron, Guillaume ; Pichard, Alexandre

AbstractSome patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts,177Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt’s lymphoma) cell xenografts,177Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement,177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.

100 Deals associated with PD-0166285

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Vascular restenosis	Phase 2	United States	Pfizer Inc.	-
Atherosclerosis	Preclinical	United States	Parke-Davis & Co. Ltd.	01 Dec 1997
Coronary Restenosis	Preclinical	United States	Parke-Davis & Co. Ltd.	01 Dec 1997
Neoplasms	Preclinical	United States	Parke-Davis & Co. Ltd.	01 Dec 1997
Solid tumor	Discovery	China	Sun Yat-Sen University	12 Jul 2024

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