1070790-89-4Relevant articles and documents
Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer
Frame, Sheelagh,Saladino, Chiara,MacKay, Craig,Atrash, Butrus,Sheldrake, Peter,McDonald, Edward,Clarkeid, Paul A.,Workman, Paul,Blake, David,Zheleva, DaniellaZ
, (2020)
Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the prosurvival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9-or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
PROCESS FOR PREPARING PURINE DERIVATIVES
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Page/Page column 32-33, (2018/08/20)
The present invention relates to a process for preparing a compound of formula [I], said process comprising the steps of: formula [II]+formula [III]?>formula [I] (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof, and optionally (d) a base; (ii) heating said reaction mixture to a temperature of at least about 150°C to form a compound of formula [I]; (iii) isolating said compound of formula [I]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (A) where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I].
CRYSTALLINE FORMS OF A PURINE DERIVATIVE
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Page/Page column 53-54, (2011/08/08)
The present invention relates to new crystalline forms of a purine derivative which exhibits excellent anti-tumour activity. The invention also relates to a pharmaceutical composition containing said crystalline forms as an active ingredient, and use ther
