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Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    is an antiapoptotic protein. Compared to other antiapoptotic proteins, the expression of Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    is common in solid tumors and, to an extent, in some leukemias and lymphomas. The overexpression of Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    is also linked to survival and chemoresistance in cancer and senescent cells. Therefore, Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    is a promising anticancer and senolytic target. Various nanomolar range Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    inhibitors have been developed.\n                    <jats:bold>ABT\u2010263<\/jats:bold>\n                    was successfully identified as a Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    \/Bcl\u20102 dual inhibitor. But it failed in the clinical trial (phase\u2010II) because of its on\u2010target platelet toxicity, which also implies an essential role of Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    protein in the survival of human platelets. Classical Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    inhibitor designs utilize occupancy\u2010driven pharmacology with typical shortcomings (such as dose\u2010dependent off\u2010target and on\u2010target platelet toxicities). Hence, event\u2010driven pharmacology\u2010based approaches, such as\n                    <jats:italic>pr<\/jats:italic>\n                    oteolysis\n                    <jats:italic>ta<\/jats:italic>\n                    rgeting\n                    <jats:italic>c<\/jats:italic>\n                    himeras (PROTACs) and SNIPERs (\n                    <jats:italic>s<\/jats:italic>\n                    pecific\n                    <jats:italic>n<\/jats:italic>\n                    on\u2010genetic\n                    <jats:italic>I<\/jats:italic>\n                    AP\u2010based\n                    <jats:italic>p<\/jats:italic>\n                    rotein\n                    <jats:italic>er<\/jats:italic>\n                    asers) have been developed. The development of Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    based PROTACs was expected, as 600 E3\u2010ligases are available in humans, while some (such as cereblon (CRBN), von Hippel\u2010Lindau (VHL)) are relatively less expressed in platelets. Therefore, E3 ligase ligand\u2010based Bcl\u2010x\n                    <jats:sub>L<\/jats:sub>\n                    PROTACs (CRBN: XZ424, XZ739; VHL: DT2216, PZ703b, 753b) showed a significant improvement in platelet therapeutic index than their parent molecules (\n                    <jats:bold>ABT\u2010263<\/jats:bold>\n                    : DT2216, PZ703b, 753b, XZ739, PZ15227;\n                    <jats:bold>A1155463<\/jats:bold>\n                    : XZ424). Other than their distinctive pharmacology, PROTACs are molecularly large, which limits their cell permeability and plays a role in improving their cell selectivity. We also discuss prodrug\u2010based approaches, such as antibody\u2010drug conjugates (\n                    <jats:bold>ABBV\u2010155<\/jats:bold>\n                    ), phosphate prodrugs (\n                    <jats:bold>APG\u20101252<\/jats:bold>\n                    ), dendrimer conjugate (\n                    <jats:bold>AZD0466<\/jats:bold>\n                    ), and glycosylated conjugates (\n                    <jats:bold>Nav\u2010Gal<\/jats:bold>\n                    ). Studies of\n                    <jats:italic>in\u2010vitro<\/jats:italic>\n                    ,\n                    <jats:italic>in\u2010vivo<\/jats:italic>\n                    , structure\u2010activity relationships, biophysical characterization, and status of preclinical\/clinical inhibitors derived from these strategies are also discussed in the review.\n                  <\/jats:p>","DOI":"10.1002\/cbic.202100689","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T12:29:53Z","timestamp":1646828993000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Strategies to Reduce the On\u2010Target Platelet Toxicity of Bcl\u2010x\n                    <sub>L<\/sub>\n                    Inhibitors: PROTACs, SNIPERs and Prodrug\u2010Based Approaches"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0341-9291","authenticated-orcid":false,"given":"Arvind","family":"Negi","sequence":"first","affiliation":[{"name":"Department of Bioproduct and Biosystems Aalto University  FI-00076 Espoo Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5564-2244","authenticated-orcid":false,"given":"Anne Sophie","family":"Voisin\u2010Chiret","sequence":"additional","affiliation":[{"name":"Normandie University UNICAEN, CERMN  14000 Caen France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,19]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.113038"},{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2017.08.004"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389557511313050004"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008730"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/943648"},{"key":"e_1_2_6_6_1","first-page":"6101","volume":"60","author":"Amundson S. 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