The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Robert L Margolis - One of the best experts on this subject based on the ideXlab platform.
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prc1 is a microtubule binding and bundling protein essential to maintain the mitotic spindle midzone
Journal of Cell Biology, 2002Co-Authors: Cristiana Mollinari, Jean-philippe Kleman, Wei Jiang, Guy Schoehn, Tony Hunter, Robert L MargolisAbstract:Midzone microtubules of mammalian Cells play an essential role in the induction of Cell Cleavage, serving as a platform for a number of proteins that play a part in cytokinesis. We demonstrate that PRC1, a mitotic spindle-associated Cdk substrate that is essential to Cell Cleavage, is a microtubule binding and bundling protein both in vivo and in vitro. Overexpression of PRC1 extensively bundles interphase microtubules, but does not affect early mitotic spindle organization. PRC1 contains two Cdk phosphorylation motifs, and phosphorylation is possibly important to mitotic suppression of bundling, as a Cdk phosphorylation-null mutant causes extensive bundling of the prometaphase spindle. Complete suppression of PRC1 by siRNA causes failure of microtubule interdigitation between half spindles and the absence of a spindle midzone. Truncation mutants demonstrate that the NH 2 -terminal region of PRC1, rich in α-helical sequence, is important for localization to the Cleavage furrow and to the center of the midbody, whereas the central region, with the highest sequence homology between species, is required for microtubule binding and bundling activity. We conclude that PRC1 is a microtubule-associated protein required to maintain the spindle midzone, and that distinct functions are associated with modular elements of the primary sequence.
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human survivin is a kinetochore associated passenger protein
Journal of Cell Biology, 2000Co-Authors: Dimitrios A Skoufias, Cristiana Mollinari, Francoise B Lacroix, Robert L MargolisAbstract:Survivin, a dimeric baculovirus inhibitor of apoptosis repeat (BIR) motif protein that is principally expressed in G2 and mitosis, has been associated with protection against apoptosis of Cells that exit mitosis aberrantly. Mammalian survivin has been reported to associate with centrosomes and with the mitotic spindle. We have expressed a human hemagglutinin-tagged survivin plasmid to determine its localization, and find instead that it clearly acts as a passenger protein. In HeLa Cells, survivin first associates with the kinetochores, and then translocates to the spindle midzone during anaphase and, finally, to the midbody during Cell Cleavage. Its localization is similar to that of TD-60, a known passenger protein. Both a point mutation in the baculovirus IAP repeat motif (C84A) and a COOH-terminal deletion mutant (Δ106) of survivin fail to localize to either kinetochores or midbodies, but neither interferes with Cell Cleavage. The interphase localization of survivin is Cell cycle regulated since in permanently transfected NIH3T3 Cells it is excluded from the nuclei until G2, where it localizes with centromeres. Survivin remains associated with mitotic kinetochores when microtubule assembly is disrupted and its localization is thus independent of microtubules. We conclude that human survivin is positioned to have an important function in the mechanism of Cell Cleavage.
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delay of hela Cell Cleavage into interphase using dihydrocytochalasin b retention of a postmitotic spindle and telophase disc correlates with synchronous Cleavage recovery
Journal of Cell Biology, 1995Co-Authors: S N Martineau, Paul R. Andreassen, Robert L MargolisAbstract:The molecular signals that determine the position and timing of the Cleavage furrow during mammalian Cell cytokinesis are presently unknown. We have studied in detail the effect of dihydrocytochalasin B (DCB), a drug that interferes with actin assembly, on specific late mitotic events in synchronous HeLa Cells. When Cleavage furrow formation is blocked at 10 microM DCB, Cells return to interphase by the criteria of reformation of nuclei with lamin borders, degradation of the cyclin B component of p34cdc2 kinase, and loss of mitosis specific MPM-2 antigens. However, the machinery for Cell Cleavage is retained for up to one hour into G1 when Cleavage cannot proceed. The components retained consist prominently of a "postmitotic" spindle and a telophase disc, a structure templated by the mitotic spindle in anaphase that may determine the position and timing of the Cleavage furrow. Upon release from DCB block, G1 Cells proceed through a rapid and synchronous Cleavage. We conclude that the mitotic spindle is not inevitably destroyed at the end of mitosis, but persists as an integral structure with the telophase disc in the absence of Cleavage. We also conclude that Cell Cleavage can occur in G1, and is therefore an event metabolically independent of mitosis. The retained telophase disc may indeed signal the position of furrow formation, as G1 Cleavage occurs only in the position where the retained disc underlies the Cell cortex. The protocol we describe should now enable development of a model system for the study of mammalian Cell Cleavage as a synchronous event independent of mitosis.
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hypothesis the telophase disc its possible role in mammalian Cell Cleavage
BioEssays, 1993Co-Authors: Robert L Margolis, Paul R. AndreassenAbstract:The molecular signals that determine the position and timing of the furrow that forms during mammalian Cell cytokinesis are presently unknown. It is apparent, however, that these signals are generated by the mitotic spindle after the onset of anaphase. Recently we have described a structure that bisects the Cell during telophase at the position of the cytokinetic furrow. This structure, the telephase disc, appears to the templated by the motitc spindle during anaphase, and precedes the formation of the cytokinetic furrow. The relationship of the telephase disc to the myosin and actin based furrowing mechanism is discussed here. We propose that the telophase disc may determine the position and timing of Cleavage by recruitment and alignment of myosin.
Paul R. Andreassen - One of the best experts on this subject based on the ideXlab platform.
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the mammalian passenger protein td 60 is an rcc1 family member with an essential role in prometaphase to metaphase progression
Developmental Cell, 2003Co-Authors: Cristiana Mollinari, Stephanie Martineauthuillier, Solange Monier, Sylvie Kieffer, Annick Boulet, Paul R. Andreassen, Bruno Goud, Caroline Reynaud, Jerome Garin, Jean-philippe KlemanAbstract:Abstract Passenger proteins migrate from inner centromeres to the spindle midzone during late mitosis, and those described to date are essential both for proper chromosome segregation and for completion of Cell Cleavage. We have purified and cloned the human passenger protein TD-60, and we here report that it is a member of the RCC1 family and that it binds preferentially the nucleotide-free form of the small G protein Rac1. Using siRNA, we further demonstrate that the absence of TD-60 substantially suppresses overall spindle assembly, blocks Cells in prometaphase, and activates the spindle assembly checkpoint. These defects suggest TD-60 may have a role in global spindle assembly or may be specifically required to integrate kinetochores into the mitotic spindle. The latter is consistent with a TD-60 requirement for recruitment of the passenger proteins survivin and Aurora B, and suggests that like other passenger proteins, TD-60 is involved in regulation of Cell Cleavage.
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delay of hela Cell Cleavage into interphase using dihydrocytochalasin b retention of a postmitotic spindle and telophase disc correlates with synchronous Cleavage recovery
Journal of Cell Biology, 1995Co-Authors: S N Martineau, Paul R. Andreassen, Robert L MargolisAbstract:The molecular signals that determine the position and timing of the Cleavage furrow during mammalian Cell cytokinesis are presently unknown. We have studied in detail the effect of dihydrocytochalasin B (DCB), a drug that interferes with actin assembly, on specific late mitotic events in synchronous HeLa Cells. When Cleavage furrow formation is blocked at 10 microM DCB, Cells return to interphase by the criteria of reformation of nuclei with lamin borders, degradation of the cyclin B component of p34cdc2 kinase, and loss of mitosis specific MPM-2 antigens. However, the machinery for Cell Cleavage is retained for up to one hour into G1 when Cleavage cannot proceed. The components retained consist prominently of a "postmitotic" spindle and a telophase disc, a structure templated by the mitotic spindle in anaphase that may determine the position and timing of the Cleavage furrow. Upon release from DCB block, G1 Cells proceed through a rapid and synchronous Cleavage. We conclude that the mitotic spindle is not inevitably destroyed at the end of mitosis, but persists as an integral structure with the telophase disc in the absence of Cleavage. We also conclude that Cell Cleavage can occur in G1, and is therefore an event metabolically independent of mitosis. The retained telophase disc may indeed signal the position of furrow formation, as G1 Cleavage occurs only in the position where the retained disc underlies the Cell cortex. The protocol we describe should now enable development of a model system for the study of mammalian Cell Cleavage as a synchronous event independent of mitosis.
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hypothesis the telophase disc its possible role in mammalian Cell Cleavage
BioEssays, 1993Co-Authors: Robert L Margolis, Paul R. AndreassenAbstract:The molecular signals that determine the position and timing of the furrow that forms during mammalian Cell cytokinesis are presently unknown. It is apparent, however, that these signals are generated by the mitotic spindle after the onset of anaphase. Recently we have described a structure that bisects the Cell during telophase at the position of the cytokinetic furrow. This structure, the telephase disc, appears to the templated by the motitc spindle during anaphase, and precedes the formation of the cytokinetic furrow. The relationship of the telephase disc to the myosin and actin based furrowing mechanism is discussed here. We propose that the telophase disc may determine the position and timing of Cleavage by recruitment and alignment of myosin.
Iontcho R. Vlahov - One of the best experts on this subject based on the ideXlab platform.
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abstract 757 novel warheads for targeted therapies of cancer the concept and design of oxime ether based pro pbds
Cancer Research, 2018Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Jeremy F. Vaughn, Spencer Hahn, Ning Zou, Kevin K W Wang, Christopher P LeamonAbstract:Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antibiotics are a class of natural products produced by various actinomycetes bacteria. PBD-dimers function as sequence-selective DNA-crosslinking, alkylating compounds which are considerably more potent than systemic chemotherapeutic agents. PBDs recognize and bond to specific sequences in the DNA minor groove. After DNA insertion, a covalent aminal bond is formed through nucleophilic attack of the N-2 of a guanine (G) base on the electrophilic C-11 imine of PBD. The end result is obstruction of tumor Cell division without any significant distortion of the DNA9s helical structure, thus potentially avoiding the common phenomenon of drug resistance. In recent years, synthetic PBD-dimers have emerged as a promising class of payloads for conjugates in the field of targeted cancer therapies. Unfortunately, many PBD conjugates preserve the strongly alkylating (electrophilic C-11) imine moiety within their structural framework, which can react in a deleterious manner while in circulation on their way to their intended targets. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine functionality. In our design concept, we replaced this moiety with its synthetic precursors: an aldehyde and an amine. The later provided an attachment point to targeting ligands through self-immolative linker systems, whereas the former was masked as an oxime ether. Such oxime ethers are known to exhibit enhanced stability under physiological conditions. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of an aromatic amine. As we discovered, an intramolecular ring-closure subsequently takes place as the aromatic amine adds directly into the sp2 center of the oxime ether to form the imine condensate and ultimately the 1,4-diazepine ring in a PBD framework. In our pro-PBDs, we envision exploiting their aromatic amines as a part of an arsenal of self-immolative linker systems for small molecule conjugation. To prove the range of applications for this new class of latent DNA-alkylators, we modified their linkers to tailor the kinetics of prodrug release and drug formation. The utility of these novel warheads and linker systems towards the design of Small Molecule Drug Conjugates (SMDC) for targeted cancer therapies will also be discussed in the presented poster. One can predict that any of the presented pro-PBDs could be easily incorporated as novel payloads in Antibody-Drug Conjugates (ADCs). Citation Format: Iontcho Vlahov, Albert Felten, Ning Zou, Kevin Wang, Hari K. Santhapuram, Paul Kleindl, Spencer Hahn, Jeremy Vaughn, Christopher Leamon. Novel warheads for targeted therapies of cancer: The concept and design of oxime-ether-based pro-PBDs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 757.
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latent warheads for targeted cancer therapy design and synthesis of pro pyrrolobenzodiazepines and conjugates
Bioconjugate Chemistry, 2017Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Garth L. Parham, Kevin Wang, Fei You, Jeremy F. Vaughn, Spencer Hahn, Hanna F KleinAbstract:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody–drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative l...
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Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates
2017Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Garth L. Parham, Kevin Wang, Fei You, Jeremy F. Vaughn, Spencer J. HahnAbstract:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody–drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed exCellent biological activity and specificity
Paul J. Kleindl - One of the best experts on this subject based on the ideXlab platform.
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abstract 757 novel warheads for targeted therapies of cancer the concept and design of oxime ether based pro pbds
Cancer Research, 2018Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Jeremy F. Vaughn, Spencer Hahn, Ning Zou, Kevin K W Wang, Christopher P LeamonAbstract:Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antibiotics are a class of natural products produced by various actinomycetes bacteria. PBD-dimers function as sequence-selective DNA-crosslinking, alkylating compounds which are considerably more potent than systemic chemotherapeutic agents. PBDs recognize and bond to specific sequences in the DNA minor groove. After DNA insertion, a covalent aminal bond is formed through nucleophilic attack of the N-2 of a guanine (G) base on the electrophilic C-11 imine of PBD. The end result is obstruction of tumor Cell division without any significant distortion of the DNA9s helical structure, thus potentially avoiding the common phenomenon of drug resistance. In recent years, synthetic PBD-dimers have emerged as a promising class of payloads for conjugates in the field of targeted cancer therapies. Unfortunately, many PBD conjugates preserve the strongly alkylating (electrophilic C-11) imine moiety within their structural framework, which can react in a deleterious manner while in circulation on their way to their intended targets. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine functionality. In our design concept, we replaced this moiety with its synthetic precursors: an aldehyde and an amine. The later provided an attachment point to targeting ligands through self-immolative linker systems, whereas the former was masked as an oxime ether. Such oxime ethers are known to exhibit enhanced stability under physiological conditions. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of an aromatic amine. As we discovered, an intramolecular ring-closure subsequently takes place as the aromatic amine adds directly into the sp2 center of the oxime ether to form the imine condensate and ultimately the 1,4-diazepine ring in a PBD framework. In our pro-PBDs, we envision exploiting their aromatic amines as a part of an arsenal of self-immolative linker systems for small molecule conjugation. To prove the range of applications for this new class of latent DNA-alkylators, we modified their linkers to tailor the kinetics of prodrug release and drug formation. The utility of these novel warheads and linker systems towards the design of Small Molecule Drug Conjugates (SMDC) for targeted cancer therapies will also be discussed in the presented poster. One can predict that any of the presented pro-PBDs could be easily incorporated as novel payloads in Antibody-Drug Conjugates (ADCs). Citation Format: Iontcho Vlahov, Albert Felten, Ning Zou, Kevin Wang, Hari K. Santhapuram, Paul Kleindl, Spencer Hahn, Jeremy Vaughn, Christopher Leamon. Novel warheads for targeted therapies of cancer: The concept and design of oxime-ether-based pro-PBDs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 757.
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latent warheads for targeted cancer therapy design and synthesis of pro pyrrolobenzodiazepines and conjugates
Bioconjugate Chemistry, 2017Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Garth L. Parham, Kevin Wang, Fei You, Jeremy F. Vaughn, Spencer Hahn, Hanna F KleinAbstract:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody–drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative l...
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Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates
2017Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Garth L. Parham, Kevin Wang, Fei You, Jeremy F. Vaughn, Spencer J. HahnAbstract:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody–drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed exCellent biological activity and specificity
Jeremy F. Vaughn - One of the best experts on this subject based on the ideXlab platform.
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abstract 757 novel warheads for targeted therapies of cancer the concept and design of oxime ether based pro pbds
Cancer Research, 2018Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Jeremy F. Vaughn, Spencer Hahn, Ning Zou, Kevin K W Wang, Christopher P LeamonAbstract:Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antibiotics are a class of natural products produced by various actinomycetes bacteria. PBD-dimers function as sequence-selective DNA-crosslinking, alkylating compounds which are considerably more potent than systemic chemotherapeutic agents. PBDs recognize and bond to specific sequences in the DNA minor groove. After DNA insertion, a covalent aminal bond is formed through nucleophilic attack of the N-2 of a guanine (G) base on the electrophilic C-11 imine of PBD. The end result is obstruction of tumor Cell division without any significant distortion of the DNA9s helical structure, thus potentially avoiding the common phenomenon of drug resistance. In recent years, synthetic PBD-dimers have emerged as a promising class of payloads for conjugates in the field of targeted cancer therapies. Unfortunately, many PBD conjugates preserve the strongly alkylating (electrophilic C-11) imine moiety within their structural framework, which can react in a deleterious manner while in circulation on their way to their intended targets. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine functionality. In our design concept, we replaced this moiety with its synthetic precursors: an aldehyde and an amine. The later provided an attachment point to targeting ligands through self-immolative linker systems, whereas the former was masked as an oxime ether. Such oxime ethers are known to exhibit enhanced stability under physiological conditions. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of an aromatic amine. As we discovered, an intramolecular ring-closure subsequently takes place as the aromatic amine adds directly into the sp2 center of the oxime ether to form the imine condensate and ultimately the 1,4-diazepine ring in a PBD framework. In our pro-PBDs, we envision exploiting their aromatic amines as a part of an arsenal of self-immolative linker systems for small molecule conjugation. To prove the range of applications for this new class of latent DNA-alkylators, we modified their linkers to tailor the kinetics of prodrug release and drug formation. The utility of these novel warheads and linker systems towards the design of Small Molecule Drug Conjugates (SMDC) for targeted cancer therapies will also be discussed in the presented poster. One can predict that any of the presented pro-PBDs could be easily incorporated as novel payloads in Antibody-Drug Conjugates (ADCs). Citation Format: Iontcho Vlahov, Albert Felten, Ning Zou, Kevin Wang, Hari K. Santhapuram, Paul Kleindl, Spencer Hahn, Jeremy Vaughn, Christopher Leamon. Novel warheads for targeted therapies of cancer: The concept and design of oxime-ether-based pro-PBDs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 757.
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latent warheads for targeted cancer therapy design and synthesis of pro pyrrolobenzodiazepines and conjugates
Bioconjugate Chemistry, 2017Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Garth L. Parham, Kevin Wang, Fei You, Jeremy F. Vaughn, Spencer Hahn, Hanna F KleinAbstract:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody–drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative l...
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Latent Warheads for Targeted Cancer Therapy: Design and Synthesis of pro-Pyrrolobenzodiazepines and Conjugates
2017Co-Authors: Iontcho R. Vlahov, Paul J. Kleindl, Hari K. Santhapuram, Albert Felten, Garth L. Parham, Kevin Wang, Fei You, Jeremy F. Vaughn, Spencer J. HahnAbstract:Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody–drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted Cell, Cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed exCellent biological activity and specificity