Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment
Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by 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 CLK3 with...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-11, Vol.67 (21), p.18895-18910 |
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| creator | Brettell, Skye B Janha, Omar Begen, Abbey Cann, Gillian Sharma, Saumya Olaniyan, Niniola Yelland, Tamas Hole, Alison J Alam, Benazir Mayville, Emily Gillespie, Ross Capper, Michael Fidock, David A Milligan, Graeme Clarke, David J Tobin, Andrew B Jamieson, Andrew G |
| description | Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by
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
CLK3 with the reversible inhibitor TCMDC-135051 (
), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide
shows nanomolar potency and covalent inhibition in both recombinant protein and
assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally,
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
is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure. |
| doi_str_mv | 10.1021/acs.jmedchem.4c01300 |
| format | Article |
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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
CLK3 with the reversible inhibitor TCMDC-135051 (
), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide
shows nanomolar potency and covalent inhibition in both recombinant protein and
assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally,
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
is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c01300</identifier><identifier>PMID: 39441986</identifier><language>eng</language><publisher>United States</publisher><ispartof>Journal of medicinal chemistry, 2024-11, Vol.67 (21), p.18895-18910</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c686-46ce872c18139da6e7f4df3cd156cd61a83eb14e2b3a3834e2cbf9fe42200b2f3</cites><orcidid>0000-0002-1807-3123 ; 0000-0003-1726-7353 ; 0000-0002-6946-3519 ; 0000-0003-0102-6993 ; 0009-0003-4026-916X ; 0000-0002-3741-2952</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2765,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39441986$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brettell, Skye B</creatorcontrib><creatorcontrib>Janha, Omar</creatorcontrib><creatorcontrib>Begen, Abbey</creatorcontrib><creatorcontrib>Cann, Gillian</creatorcontrib><creatorcontrib>Sharma, Saumya</creatorcontrib><creatorcontrib>Olaniyan, Niniola</creatorcontrib><creatorcontrib>Yelland, Tamas</creatorcontrib><creatorcontrib>Hole, Alison J</creatorcontrib><creatorcontrib>Alam, Benazir</creatorcontrib><creatorcontrib>Mayville, Emily</creatorcontrib><creatorcontrib>Gillespie, Ross</creatorcontrib><creatorcontrib>Capper, Michael</creatorcontrib><creatorcontrib>Fidock, David A</creatorcontrib><creatorcontrib>Milligan, Graeme</creatorcontrib><creatorcontrib>Clarke, David J</creatorcontrib><creatorcontrib>Tobin, Andrew B</creatorcontrib><creatorcontrib>Jamieson, Andrew G</creatorcontrib><title>Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by
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
CLK3 with the reversible inhibitor TCMDC-135051 (
), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide
shows nanomolar potency and covalent inhibition in both recombinant protein and
assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally,
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
is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure.</description><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNo90MlOwzAQgGELgWgpvAFCfoGU8VLX4VZFLBVlEeQeOc64TZU0yDZFfXuC2nKakUb_HD5CrhmMGXB2a2wYr1us7ArbsbTABMAJGbIJh0RqkKdkCMB5whUXA3IRwhoABOPinAxEKiVLtRqSj9z4JcZ6s6TvjmaLZ0F_6riiWbc1DW4inW9WdVnHzoc7OqOv3RYb-hm9ibjcUdd5-mIa42tDc48mtn1ySc6caQJeHeaI5A_3efaULN4e59lskVilVSKVRT3llmkm0soonDpZOWErNlG2UsxogSWTyEthhBb9YkuXOpScA5TciRGR-7fWdyF4dMWXr1vjdwWD4k-o6IWKo1BxEOqzm3329V32t__oSCJ-Adm8ZT0</recordid><startdate>20241114</startdate><enddate>20241114</enddate><creator>Brettell, Skye B</creator><creator>Janha, Omar</creator><creator>Begen, Abbey</creator><creator>Cann, Gillian</creator><creator>Sharma, Saumya</creator><creator>Olaniyan, Niniola</creator><creator>Yelland, Tamas</creator><creator>Hole, Alison J</creator><creator>Alam, Benazir</creator><creator>Mayville, Emily</creator><creator>Gillespie, Ross</creator><creator>Capper, Michael</creator><creator>Fidock, David A</creator><creator>Milligan, Graeme</creator><creator>Clarke, David J</creator><creator>Tobin, Andrew B</creator><creator>Jamieson, Andrew G</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-1807-3123</orcidid><orcidid>https://orcid.org/0000-0003-1726-7353</orcidid><orcidid>https://orcid.org/0000-0002-6946-3519</orcidid><orcidid>https://orcid.org/0000-0003-0102-6993</orcidid><orcidid>https://orcid.org/0009-0003-4026-916X</orcidid><orcidid>https://orcid.org/0000-0002-3741-2952</orcidid></search><sort><creationdate>20241114</creationdate><title>Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment</title><author>Brettell, Skye B ; Janha, Omar ; Begen, Abbey ; Cann, Gillian ; Sharma, Saumya ; Olaniyan, Niniola ; Yelland, Tamas ; Hole, Alison J ; Alam, Benazir ; Mayville, Emily ; Gillespie, Ross ; Capper, Michael ; Fidock, David A ; Milligan, Graeme ; Clarke, David J ; Tobin, Andrew B ; Jamieson, Andrew G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c686-46ce872c18139da6e7f4df3cd156cd61a83eb14e2b3a3834e2cbf9fe42200b2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brettell, Skye B</creatorcontrib><creatorcontrib>Janha, Omar</creatorcontrib><creatorcontrib>Begen, Abbey</creatorcontrib><creatorcontrib>Cann, Gillian</creatorcontrib><creatorcontrib>Sharma, Saumya</creatorcontrib><creatorcontrib>Olaniyan, Niniola</creatorcontrib><creatorcontrib>Yelland, Tamas</creatorcontrib><creatorcontrib>Hole, Alison J</creatorcontrib><creatorcontrib>Alam, Benazir</creatorcontrib><creatorcontrib>Mayville, Emily</creatorcontrib><creatorcontrib>Gillespie, Ross</creatorcontrib><creatorcontrib>Capper, Michael</creatorcontrib><creatorcontrib>Fidock, David A</creatorcontrib><creatorcontrib>Milligan, Graeme</creatorcontrib><creatorcontrib>Clarke, David J</creatorcontrib><creatorcontrib>Tobin, Andrew B</creatorcontrib><creatorcontrib>Jamieson, Andrew G</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brettell, Skye B</au><au>Janha, Omar</au><au>Begen, Abbey</au><au>Cann, Gillian</au><au>Sharma, Saumya</au><au>Olaniyan, Niniola</au><au>Yelland, Tamas</au><au>Hole, Alison J</au><au>Alam, Benazir</au><au>Mayville, Emily</au><au>Gillespie, Ross</au><au>Capper, Michael</au><au>Fidock, David A</au><au>Milligan, Graeme</au><au>Clarke, David J</au><au>Tobin, Andrew B</au><au>Jamieson, Andrew G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2024-11-14</date><risdate>2024</risdate><volume>67</volume><issue>21</issue><spage>18895</spage><epage>18910</epage><pages>18895-18910</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by
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
CLK3 with the reversible inhibitor TCMDC-135051 (
), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide
shows nanomolar potency and covalent inhibition in both recombinant protein and
assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally,
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
is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure.</abstract><cop>United States</cop><pmid>39441986</pmid><doi>10.1021/acs.jmedchem.4c01300</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-1807-3123</orcidid><orcidid>https://orcid.org/0000-0003-1726-7353</orcidid><orcidid>https://orcid.org/0000-0002-6946-3519</orcidid><orcidid>https://orcid.org/0000-0003-0102-6993</orcidid><orcidid>https://orcid.org/0009-0003-4026-916X</orcidid><orcidid>https://orcid.org/0000-0002-3741-2952</orcidid></addata></record> |
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| title | Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment |
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