A Multicenter Phase 1 Ascending Dose Study of DCC-2701 To Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Patients With Advanced Solid Tumors

The main purpose of this study is to investigate the safety of the investigational drug DCC-2701 and whether it will work to help people who have advanced solid tumors or cancer that has spread to other parts of the body.

Start Date01 Jun 2014

Sponsor / Collaborator

Deciphera Pharmaceuticals, Inc.

100 Clinical Results associated with PfCLK3

100 Translational Medicine associated with PfCLK3

0 Patents (Medical) associated with PfCLK3

Literatures (Medical) associated with PfCLK3

03 Aug 2022·Science Translational MedicineQ1 · MEDICINE

Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase

Q1 · MEDICINE

Article

Author: Bellini, Valeria ; Bowler, Matthew W. ; Brenier-Pinchart, Marie-Pierre ; Belmudes, Lucid ; Laurent, Fabrice ; Flore, Nardella ; Scherf, Artur ; Couté, Yohann ; Mas, Caroline ; Hakimi, Mohamed-Ali ; Bougdour, Alexandre ; Cannella, Dominique ; Swale, Christopher

The Apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that include Toxoplasma gondii , Plasmodium , and Cryptosporidium spp., which infect humans and animals and cause severe parasitic diseases. Available therapeutics against these diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. We use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index when used against T. gondii . We have identified Tg PRP4K of T. gondii as the primary target of altiratinib using genetic target deconvolution, which highlighted key residues within the kinase catalytic site that conferred drug resistance when mutated. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for Tg PRP4K and for its Plasmodium falciparum counterpart, Pf CLK3. Our data identified structural features critical for binding of the other Pf CLK3 inhibitor, TCMDC-135051. Consistent with the splicing control activity of this kinase family, we have shown that altiratinib can cause global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum . Thus, our data establish parasitic PRP4K/CLK3 as a potential pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.

Nature CommunicationsQ1 · CROSS-FIELD

Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum

Q1 · CROSS-FIELD

ArticleOA

Author: Marie-Paule Nivez ; Yvan Bouza ; Michele Graciotti ; Abdirhaman Abdi ; Jean-Phillipe Semblat ; Sylvain Eschenlauer ; Shruti Agarwal ; Andrew B Tobin ; Jean Halbert ; Selina Kern ; Dominique Dorin-Semblat ; Christian D Doerig ; Zoe Holland ; Luc Reininger ; Audrey Sicard ; Pushkar Sharma ; Claudia Demarta ; Mahmood M Alam ; Andrew R Bottrill ; Sharad Mistry ; Tenzing Lama ; Divya Catherine Thomas ; Gabriele Pradel ; Lev Solyakov ; Clare Fennell

The role of protein phosphorylation in the life cycle of malaria parasites is slowly emerging. Here we combine global phospho-proteomic analysis with kinome-wide reverse genetics to assess the importance of protein phosphorylation in Plasmodium falciparum asexual proliferation. We identify 1177 phosphorylation sites on 650 parasite proteins that are involved in a wide range of general cellular activities such as DNA synthesis, transcription and metabolism as well as key parasite processes such as invasion and cyto-adherence. Several parasite protein kinases are themselves phosphorylated on putative regulatory residues, including tyrosines in the activation loop of PfGSK3 and PfCLK3; we show that phosphorylation of PfCLK3 Y526 is essential for full kinase activity. A kinome-wide reverse genetics strategy identified 36 parasite kinases as likely essential for erythrocytic schizogony. These studies not only reveal processes that are regulated by protein phosphorylation, but also define potential anti-malarial drug targets within the parasite kinome.

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