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

2020-09-10·Journal of Medicinal Chemistry1区 · 医学

Development of Potent PfCLK3 Inhibitors Based on TCMDC-135051 as a New Class of Antimalarials

1区 · 医学

Article

作者: Alam, Mahmood M. ; Sanchez-Azqueta, Ana ; Mapesa, Kopano ; Tobin, Andrew B. ; Nwakanma, Davis C. ; Amambua-Ngwa, Alfred ; Janha, Omar ; Mahindra, Amit ; Jamieson, Andrew G.

The protein kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum. We recently validated PfCLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we describe the synthesis of our initial hit TCMDC-135051 (1) and efforts to establish a structure-activity relationship with a 7-azaindole-based series. A total of 14 analogues were assessed in a time-resolved fluorescence energy transfer assay against the full-length recombinant protein kinase PfCLK3, and 11 analogues were further assessed in asexual 3D7 (chloroquine-sensitive) strains of P. falciparum parasites. SAR relating to rings A and B was established. These data together with analysis of activity against parasites collected from patients in the field suggest that TCMDC-135051 (1) is a promising lead compound for the development of new antimalarials with a novel mechanism of action targeting PfCLK3.

Journal of Medicinal Chemistry

Targeting PfCLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment

Article

作者: Alam, Benazir ; Mayville, Emily ; Hole, Alison J. ; Fidock, David A. ; Yelland, Tamas ; Brettell, Skye B. ; Janha, Omar ; Jamieson, Andrew G. ; Gillespie, Ross ; Olaniyan, Niniola ; Sharma, Saumya ; Milligan, Graeme ; Tobin, Andrew B. ; Cann, Gillian ; Capper, Michael ; Clarke, David J. ; Begen, Abbey

Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by Plasmodium falciparum increasing this number each year. New medicines with novel mechanisms of action are, therefore, urgently needed. In this work, we solved the cocrystal structure of the essential malarial kinase PfCLK3 with the reversible inhibitor TCMDC-135051 (1), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide 4 shows nanomolar potency and covalent inhibition in both recombinant protein and P. falciparum assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally, 4 showed improved kinase selectivity and a high selectivity index against HepG2 cells, with a low propensity for resistance (log MIR > 8.1). To our knowledge, compound 4 is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure.

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适应症	最高研发状态	国家/地区	公司	日期
恶性疟	临床前	英国	GSK Plc	-
恶性疟	临床前	巴西	University of Campinas	-
恶性疟	临床前	美国	Novartis Institutes for Biomedical Research, Inc.	-