La presente invention concerne de nouveaux derives d'acridine de formule (I), ou leurs sels p... more La presente invention concerne de nouveaux derives d'acridine de formule (I), ou leurs sels pharmaceutiquement acceptables, qui sont des inhibiteurs de la fonction de l'enzyme telomerase. Ces composes sont utiles pour le traitement des troubles de la proliferation cellulaire, tels que le cancer.
Un conjugado que contiene maitansina de la formula general: **(Ver formula)** en en la que D repr... more Un conjugado que contiene maitansina de la formula general: **(Ver formula)** en en la que D representa una unidad estructural de maitansina; q representa un numero entero de 1 a 10; Lk1 representa un enlazador; m representa un numero entero de 1 a 10; P representa un enlace o un grupo z-valente -P1-NH- en el que z es de 2 a 11 y P1 es un grupo que contiene al menos una unidad de etileno -CH2-CH2- o unidad de etilenglicol -O-CH2-CH2-; p representa un numero entero de 1 a 10; Lk2 representa un enlace o un enlazador y-valente en el que y es de 2 a 11 y que consiste en de 1 a 9 residuos de aspartato y/o glutamato; Lk3 representa un enlazador de la formula general: -CO-Ph-XY- (II) en la que Ph es un grupo fenilo opcionalmente sustituido; X representa un grupo CO o un grupo CH.OH; e Y representa un grupo de formula: **(Ver formula)** en las que cada uno de A y B representa un grupo C1-4 alquileno o alquenileno; Ab representa una proteina o peptido de enlace capaz de enlazarse a un compan...
La presente invention concerne de nouveaux composes de formule (I) dans laquelle: X, Q, R 1 , R 2... more La presente invention concerne de nouveaux composes de formule (I) dans laquelle: X, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 21 , R 22 et R 23 sont tels que definis dans la description. Les composes de formule (I) sont inhibiteurs de la fonction enzymatique de la telomerase et sont donc utiles pour le traitement de troubles de la proliferation cellulaire, tel que le cancer.
Preparation of antibody-drug conjugates (ADCs) with a highly homogeneous drug loading in general ... more Preparation of antibody-drug conjugates (ADCs) with a highly homogeneous drug loading in general requires site-selective conjugation of a cytotoxic payload. Typically, functionality utilized for attachment of the payload is achieved through engineering of suitable chemical handles or by enzymatic modification of the antibody. Relatively few methods to produce ADCs with homogeneous drug loading via endogenous amino acid conjugation have been developed. Herein we describe a robust method for the conjugation of antibodies using a cysteine rebridging approach to produce ADCs with highly homogeneous drug-to-antibody ratios (DAR) at the native interchain disulfides, called ThioBridge®. The process described relies upon an elegant cascade of addition-elimination reactions carried out under mild aqueous conditions that can be readily applied to wild-type antibodies without the need for prior modification via recombinant or enzymatic means. Using this method, conversions to a conserved DAR ADC are typically in the range of 70-95% and overall process yields of >70% are readily achieved.
Imidazotetrazines substituted at the N-3 position overcome resistance or tolerance to temozolomid... more Imidazotetrazines substituted at the N-3 position overcome resistance or tolerance to temozolomide conferred, respectively, by MGMT or DNA MMR defects.
Cancers with downstream activating KRAS or BRAF mutations in the EGFR pathway are resistant to EG... more Cancers with downstream activating KRAS or BRAF mutations in the EGFR pathway are resistant to EGFR targeting agents such as cetuximab and correspond to a significant unmet need. We hypothesized that an anti-EGFR ADC could be effective against KRAS or BRAF mutated tumors due to the cytotoxic mechanism of the ADC warhead. In an effort to eliminate the known dermal toxicity associated with anti-EGFR therapy, and to mitigate potential toxicities associated with treatment by an anti-EGFR ADC, a mAb was engineered with increased tumor microenvironment (TME) specificity for EGFR. The lead mAb demonstrated undetectable in vivo binding to human donor foreskins grafted onto nude mice, while binding to human A431 tumor xenografts with similar intensity to cetuximab (P < 0.005, detected using DyLight-755 conjugated versions of each mAb, measured with a Caliper IVIS system). The lead mAb was further optimized and conjugated to the potent cytotoxic drug MMAE using a novel bis-alkylating conju...
Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. ... more Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. Thus, specific small molecule inhibitors targeting ATM could perhaps be developed into efficient radiosensitizers. Recently, a specific inhibitor of the ATM kinase, KU-55933, was shown to radiosensitize human cancer cells. Herein, we report on an improved analogue of KU-55933 (KU-60019) with Ki and IC50 values half of those of KU-55933. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. As expected, KU-60019 is a highly effective radiosensitizer of human glioma cells. A-T fibroblasts were not radiosensitized by KU-60019, strongly suggesting that the ATM kinase is specifically targeted. Furthermore, KU-60019 reduced basal S473 AKT phosphorylation, suggesting that the ATM kinase might regulate a protein phosphatase acting on AKT. In line with this finding, the effect of KU-60019 on AKT phosphorylation was...
Structure-activity relationships have been investigated for inhibition of DNA-dependent protein k... more Structure-activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50=13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50=220 nM) effectively sensitized HeLa cells to the topoisomerase II inhibitor etoposide in vitro.
Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibit... more Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.
Journal of Experimental & Clinical Cancer Research, 2013
Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters... more Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment. The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant β2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay. Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with β...
The cellular response to DNA double-strand break (DSB) formation is an essential component of nor... more The cellular response to DNA double-strand break (DSB) formation is an essential component of normal cell survival, following exposure to DNA-damaging chemicals and ionising radiation. The serine/threonine kinase DNA-dependent protein kinase (DNA-PK) is a member of the phosphatidylinositol (PI) 3-kinase related kinase (PIKK) family of enzymes, and plays an important role in DNA DSB repair via the non-homologous end-joining (NHEJ) pathway. DNA-PK inhibitors may, therefore, be useful as agents to improve the activity of radio- and chemo-therapy in the treatment of cancer. Identification of the lead benzo[h]chromen-4-one DNA-PK inhibitor NU7026 (IC50 = 0.23 uM) guided the development of the potent and selective ATP-competitive chromenone NU7441 (DNA-PK IC50 = 30 nM). Structure-activity relationship studies for DNA-PK inhibition by chromenone-derivatives were conducted in conjunction with homology modelling. Library synthesis was undertaken employing a solution multiple-parallel approac...
After a brief summary of our asymmetric total syntheses of A83586C and 4-epi-A83586C, we will go ... more After a brief summary of our asymmetric total syntheses of A83586C and 4-epi-A83586C, we will go on to describe some of our synthetic work on the monamycins, and our most recent total synthesis studies on the bryostatin antitumor macrolides.
A fully stereocontrolled asymmetric synthesis of the Southern Hemisphere intermediate 426 for the... more A fully stereocontrolled asymmetric synthesis of the Southern Hemisphere intermediate 426 for the bryostatin family of antitumour agents is described in this thesis. It details how the strategy evolved from (E)-1,4-hexadiene 450 including a Roush-Masamune coupling between 462 and 507, cyclisation to glycal 505, selective epoxidation and in-situ Fischer glycosidation to 503 and an aldol / dehydration sequence to establish the (E)-exocyclic olefin. We also document a rare example of slow bond rotation in the C(18)- C(19)-bond of 426 and provide an explanation of this phenomenon. In addition, the synthesis of two truncated bryostatin analogs 525 and 526 is described, and the interaction of 525 with the CRD2 of human PKC-a discussed. [diagram].
Antibody drug conjugates (ADCs) have begun to have a tremendous impact on the treatment of cancer... more Antibody drug conjugates (ADCs) have begun to have a tremendous impact on the treatment of cancer and other pathological conditions. A current limitation in ADC development is that much effort and time is needed to fully optimise the combination of antibody, linker and drug. New linker strategies are required to ensure that more homogeneous and stable ADCs can be produced with more predictable in vivo behaviour without the need for extensive re-optimisation, especially if one component of the ADC is changed. In order to improve both the homogeneity and the stability of ADCs, we have developed linkers that allow site-specific drug conjugation based on bis-sulphones that covalently re-bridge reduced disulphide bonds. The bis-sulphone reagents comprise a drug, a linker and a bis-reactive conjugating moiety that is capable of undergoing reaction with both sulphur atoms derived from a reduced disulphide bond in antibodies and antibody fragments. We have demonstrated that the bis-sulphone...
A wide range of diseases have been shown to be influenced by the accumulation of senescent cells,... more A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer’s and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expressi...
La presente invention concerne de nouveaux derives d'acridine de formule (I), ou leurs sels p... more La presente invention concerne de nouveaux derives d'acridine de formule (I), ou leurs sels pharmaceutiquement acceptables, qui sont des inhibiteurs de la fonction de l'enzyme telomerase. Ces composes sont utiles pour le traitement des troubles de la proliferation cellulaire, tels que le cancer.
Un conjugado que contiene maitansina de la formula general: **(Ver formula)** en en la que D repr... more Un conjugado que contiene maitansina de la formula general: **(Ver formula)** en en la que D representa una unidad estructural de maitansina; q representa un numero entero de 1 a 10; Lk1 representa un enlazador; m representa un numero entero de 1 a 10; P representa un enlace o un grupo z-valente -P1-NH- en el que z es de 2 a 11 y P1 es un grupo que contiene al menos una unidad de etileno -CH2-CH2- o unidad de etilenglicol -O-CH2-CH2-; p representa un numero entero de 1 a 10; Lk2 representa un enlace o un enlazador y-valente en el que y es de 2 a 11 y que consiste en de 1 a 9 residuos de aspartato y/o glutamato; Lk3 representa un enlazador de la formula general: -CO-Ph-XY- (II) en la que Ph es un grupo fenilo opcionalmente sustituido; X representa un grupo CO o un grupo CH.OH; e Y representa un grupo de formula: **(Ver formula)** en las que cada uno de A y B representa un grupo C1-4 alquileno o alquenileno; Ab representa una proteina o peptido de enlace capaz de enlazarse a un compan...
La presente invention concerne de nouveaux composes de formule (I) dans laquelle: X, Q, R 1 , R 2... more La presente invention concerne de nouveaux composes de formule (I) dans laquelle: X, Q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 21 , R 22 et R 23 sont tels que definis dans la description. Les composes de formule (I) sont inhibiteurs de la fonction enzymatique de la telomerase et sont donc utiles pour le traitement de troubles de la proliferation cellulaire, tel que le cancer.
Preparation of antibody-drug conjugates (ADCs) with a highly homogeneous drug loading in general ... more Preparation of antibody-drug conjugates (ADCs) with a highly homogeneous drug loading in general requires site-selective conjugation of a cytotoxic payload. Typically, functionality utilized for attachment of the payload is achieved through engineering of suitable chemical handles or by enzymatic modification of the antibody. Relatively few methods to produce ADCs with homogeneous drug loading via endogenous amino acid conjugation have been developed. Herein we describe a robust method for the conjugation of antibodies using a cysteine rebridging approach to produce ADCs with highly homogeneous drug-to-antibody ratios (DAR) at the native interchain disulfides, called ThioBridge®. The process described relies upon an elegant cascade of addition-elimination reactions carried out under mild aqueous conditions that can be readily applied to wild-type antibodies without the need for prior modification via recombinant or enzymatic means. Using this method, conversions to a conserved DAR ADC are typically in the range of 70-95% and overall process yields of >70% are readily achieved.
Imidazotetrazines substituted at the N-3 position overcome resistance or tolerance to temozolomid... more Imidazotetrazines substituted at the N-3 position overcome resistance or tolerance to temozolomide conferred, respectively, by MGMT or DNA MMR defects.
Cancers with downstream activating KRAS or BRAF mutations in the EGFR pathway are resistant to EG... more Cancers with downstream activating KRAS or BRAF mutations in the EGFR pathway are resistant to EGFR targeting agents such as cetuximab and correspond to a significant unmet need. We hypothesized that an anti-EGFR ADC could be effective against KRAS or BRAF mutated tumors due to the cytotoxic mechanism of the ADC warhead. In an effort to eliminate the known dermal toxicity associated with anti-EGFR therapy, and to mitigate potential toxicities associated with treatment by an anti-EGFR ADC, a mAb was engineered with increased tumor microenvironment (TME) specificity for EGFR. The lead mAb demonstrated undetectable in vivo binding to human donor foreskins grafted onto nude mice, while binding to human A431 tumor xenografts with similar intensity to cetuximab (P < 0.005, detected using DyLight-755 conjugated versions of each mAb, measured with a Caliper IVIS system). The lead mAb was further optimized and conjugated to the potent cytotoxic drug MMAE using a novel bis-alkylating conju...
Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. ... more Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. Thus, specific small molecule inhibitors targeting ATM could perhaps be developed into efficient radiosensitizers. Recently, a specific inhibitor of the ATM kinase, KU-55933, was shown to radiosensitize human cancer cells. Herein, we report on an improved analogue of KU-55933 (KU-60019) with Ki and IC50 values half of those of KU-55933. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. As expected, KU-60019 is a highly effective radiosensitizer of human glioma cells. A-T fibroblasts were not radiosensitized by KU-60019, strongly suggesting that the ATM kinase is specifically targeted. Furthermore, KU-60019 reduced basal S473 AKT phosphorylation, suggesting that the ATM kinase might regulate a protein phosphatase acting on AKT. In line with this finding, the effect of KU-60019 on AKT phosphorylation was...
Structure-activity relationships have been investigated for inhibition of DNA-dependent protein k... more Structure-activity relationships have been investigated for inhibition of DNA-dependent protein kinase (DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC50 values were observed for pyranones and thiopyranones substituted at the 6-position, with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, and thiopyran-4-ones showed similar IC50 values against DNA-PK, whereas the pyridin-4-one system proved, in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATM inhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC50=13 nM) and revealed constrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitors identified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC50=220 nM) effectively sensitized HeLa cells to the topoisomerase II inhibitor etoposide in vitro.
Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibit... more Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.
Journal of Experimental & Clinical Cancer Research, 2013
Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters... more Quadruplexes DNA are present in telomeric DNA as well as in several cancer-related gene promoters and hence affect gene expression and subsequent biological processes. The conformations of G4 provide selective recognition sites for small molecules and thus these structures have become important drug-design targets for cancer treatment. The DNA G-quadruplex binding pentacyclic acridinium salt RHPS4 (1) has many pharmacological attributes of an ideal telomere-targeting agent but has undesirable off-target liabilities. Notably a cardiovascular effect was evident in a guinea pig model, manifested by a marked and sustained increase in QTcB interval. In accordance with this, significant interaction with the human recombinant β2 adrenergic receptor, and M1, M2 and M3 muscarinic receptors was observed, together with a high inhibition of the hERG tail current tested in a patch clamp assay. Two related pentacyclic structures, the acetylamines (2) and (3), both show a modest interaction with β...
The cellular response to DNA double-strand break (DSB) formation is an essential component of nor... more The cellular response to DNA double-strand break (DSB) formation is an essential component of normal cell survival, following exposure to DNA-damaging chemicals and ionising radiation. The serine/threonine kinase DNA-dependent protein kinase (DNA-PK) is a member of the phosphatidylinositol (PI) 3-kinase related kinase (PIKK) family of enzymes, and plays an important role in DNA DSB repair via the non-homologous end-joining (NHEJ) pathway. DNA-PK inhibitors may, therefore, be useful as agents to improve the activity of radio- and chemo-therapy in the treatment of cancer. Identification of the lead benzo[h]chromen-4-one DNA-PK inhibitor NU7026 (IC50 = 0.23 uM) guided the development of the potent and selective ATP-competitive chromenone NU7441 (DNA-PK IC50 = 30 nM). Structure-activity relationship studies for DNA-PK inhibition by chromenone-derivatives were conducted in conjunction with homology modelling. Library synthesis was undertaken employing a solution multiple-parallel approac...
After a brief summary of our asymmetric total syntheses of A83586C and 4-epi-A83586C, we will go ... more After a brief summary of our asymmetric total syntheses of A83586C and 4-epi-A83586C, we will go on to describe some of our synthetic work on the monamycins, and our most recent total synthesis studies on the bryostatin antitumor macrolides.
A fully stereocontrolled asymmetric synthesis of the Southern Hemisphere intermediate 426 for the... more A fully stereocontrolled asymmetric synthesis of the Southern Hemisphere intermediate 426 for the bryostatin family of antitumour agents is described in this thesis. It details how the strategy evolved from (E)-1,4-hexadiene 450 including a Roush-Masamune coupling between 462 and 507, cyclisation to glycal 505, selective epoxidation and in-situ Fischer glycosidation to 503 and an aldol / dehydration sequence to establish the (E)-exocyclic olefin. We also document a rare example of slow bond rotation in the C(18)- C(19)-bond of 426 and provide an explanation of this phenomenon. In addition, the synthesis of two truncated bryostatin analogs 525 and 526 is described, and the interaction of 525 with the CRD2 of human PKC-a discussed. [diagram].
Antibody drug conjugates (ADCs) have begun to have a tremendous impact on the treatment of cancer... more Antibody drug conjugates (ADCs) have begun to have a tremendous impact on the treatment of cancer and other pathological conditions. A current limitation in ADC development is that much effort and time is needed to fully optimise the combination of antibody, linker and drug. New linker strategies are required to ensure that more homogeneous and stable ADCs can be produced with more predictable in vivo behaviour without the need for extensive re-optimisation, especially if one component of the ADC is changed. In order to improve both the homogeneity and the stability of ADCs, we have developed linkers that allow site-specific drug conjugation based on bis-sulphones that covalently re-bridge reduced disulphide bonds. The bis-sulphone reagents comprise a drug, a linker and a bis-reactive conjugating moiety that is capable of undergoing reaction with both sulphur atoms derived from a reduced disulphide bond in antibodies and antibody fragments. We have demonstrated that the bis-sulphone...
A wide range of diseases have been shown to be influenced by the accumulation of senescent cells,... more A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer’s and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expressi...
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Papers by Mark Frigerio