The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy
Abstract AT‐IAP (1‐{6‐[(4‐fluorophenyl)methyl]‐3,3‐dimethyl‐1H,2H,3H‐pyrrolo[3,2‐b]pyridin‐1‐yl}‐2‐[(2R,5R)‐5‐methyl‐2‐{[(3R)‐3‐methylmorpholin‐4‐yl]methyl}piperazin‐1‐yl]ethan‐1‐one) was identified as a novel potent non‐alanine small molecule dual inhibitor of cIAP1/XIAP protein. AT‐IAP was assesse...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-12-01
|
| Series: | Pharmacology Research & Perspectives |
| Online Access: | https://doi.org/10.1002/prp2.70030 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850109466566983680 |
|---|---|
| author | Vanessa Martins George Ward Tomoko Smyth Mike Reader Gianni Chessari Chris Johnson Nicola Wilsher |
| author_facet | Vanessa Martins George Ward Tomoko Smyth Mike Reader Gianni Chessari Chris Johnson Nicola Wilsher |
| author_sort | Vanessa Martins |
| collection | DOAJ |
| description | Abstract AT‐IAP (1‐{6‐[(4‐fluorophenyl)methyl]‐3,3‐dimethyl‐1H,2H,3H‐pyrrolo[3,2‐b]pyridin‐1‐yl}‐2‐[(2R,5R)‐5‐methyl‐2‐{[(3R)‐3‐methylmorpholin‐4‐yl]methyl}piperazin‐1‐yl]ethan‐1‐one) was identified as a novel potent non‐alanine small molecule dual inhibitor of cIAP1/XIAP protein. AT‐IAP was assessed in preclinical species, demonstrating favorable bioavailability in rodent species and oral efficacy at 30 mg/kg in MDA‐MB‐231 mouse xenograft models. The major metabolic route of AT‐IAP was identified to be CYP3A driven, resulting in low oral exposure in non‐human primate (NHP) studies, given the comparatively high expression of equivalent CYP3A. AT‐IAP metabolite identification studies determined ring opening of the morpholino or piperazine moiety. An extensive campaign of optimisation resulted in increased polarity by the addition of a hydroxymethyl, which led to the identification of tolinapant (1‐(6‐[(4‐Fluorophenyl)methyl]‐5‐(hydroxymethyl)‐3,3‐dimethyl‐1 H,2 H,3 H‐pyrrolo[3,2‐ b]pyridin‐1‐yl)‐2‐[(2 R,5 R)‐5‐methyl‐2‐([(3R)‐3‐methylmorpholin‐4‐yl]methyl)piperazin‐1‐yl]ethan‐1‐one) with reduced CYP3A metabolism. Tolinapant showed oral bioavailability in rodents and NHP in the range 12–34% at 5 mg/kg. Non‐linear pharmacokinetics in NHP were observed at oral doses in the range 5–75 mg/kg. Pharmacodynamic modulation and efficacy were demonstrated in A375 mouse xenograft models at dose ranges between 5 and 20 mg/kg. On‐target engagement, as measured by reduction of cIAP 1 protein levels, was confirmed in NHP surrogate tissues and applied to target activity assessments in tolinapant phase1/2 clinical trials. |
| format | Article |
| id | doaj-art-e8c8c3ab0275432482ed48a188db291c |
| institution | OA Journals |
| issn | 2052-1707 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj-art-e8c8c3ab0275432482ed48a188db291c2025-08-20T02:38:03ZengWileyPharmacology Research & Perspectives2052-17072024-12-01126n/an/a10.1002/prp2.70030The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacyVanessa Martins0George Ward1Tomoko Smyth2Mike Reader3Gianni Chessari4Chris Johnson5Nicola Wilsher6Astex Therapeutics Limited Cambridge UKAstex Therapeutics Limited Cambridge UKAstex Therapeutics Limited Cambridge UKAstex Therapeutics Limited Cambridge UKAstex Therapeutics Limited Cambridge UKAstex Therapeutics Limited Cambridge UKAstex Therapeutics Limited Cambridge UKAbstract AT‐IAP (1‐{6‐[(4‐fluorophenyl)methyl]‐3,3‐dimethyl‐1H,2H,3H‐pyrrolo[3,2‐b]pyridin‐1‐yl}‐2‐[(2R,5R)‐5‐methyl‐2‐{[(3R)‐3‐methylmorpholin‐4‐yl]methyl}piperazin‐1‐yl]ethan‐1‐one) was identified as a novel potent non‐alanine small molecule dual inhibitor of cIAP1/XIAP protein. AT‐IAP was assessed in preclinical species, demonstrating favorable bioavailability in rodent species and oral efficacy at 30 mg/kg in MDA‐MB‐231 mouse xenograft models. The major metabolic route of AT‐IAP was identified to be CYP3A driven, resulting in low oral exposure in non‐human primate (NHP) studies, given the comparatively high expression of equivalent CYP3A. AT‐IAP metabolite identification studies determined ring opening of the morpholino or piperazine moiety. An extensive campaign of optimisation resulted in increased polarity by the addition of a hydroxymethyl, which led to the identification of tolinapant (1‐(6‐[(4‐Fluorophenyl)methyl]‐5‐(hydroxymethyl)‐3,3‐dimethyl‐1 H,2 H,3 H‐pyrrolo[3,2‐ b]pyridin‐1‐yl)‐2‐[(2 R,5 R)‐5‐methyl‐2‐([(3R)‐3‐methylmorpholin‐4‐yl]methyl)piperazin‐1‐yl]ethan‐1‐one) with reduced CYP3A metabolism. Tolinapant showed oral bioavailability in rodents and NHP in the range 12–34% at 5 mg/kg. Non‐linear pharmacokinetics in NHP were observed at oral doses in the range 5–75 mg/kg. Pharmacodynamic modulation and efficacy were demonstrated in A375 mouse xenograft models at dose ranges between 5 and 20 mg/kg. On‐target engagement, as measured by reduction of cIAP 1 protein levels, was confirmed in NHP surrogate tissues and applied to target activity assessments in tolinapant phase1/2 clinical trials.https://doi.org/10.1002/prp2.70030 |
| spellingShingle | Vanessa Martins George Ward Tomoko Smyth Mike Reader Gianni Chessari Chris Johnson Nicola Wilsher The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy Pharmacology Research & Perspectives |
| title | The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy |
| title_full | The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy |
| title_fullStr | The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy |
| title_full_unstemmed | The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy |
| title_short | The preclinical pharmacokinetics of Tolinapant—A dual cIAP1/XIAP antagonist with in vivo efficacy |
| title_sort | preclinical pharmacokinetics of tolinapant a dual ciap1 xiap antagonist with in vivo efficacy |
| url | https://doi.org/10.1002/prp2.70030 |
| work_keys_str_mv | AT vanessamartins thepreclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT georgeward thepreclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT tomokosmyth thepreclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT mikereader thepreclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT giannichessari thepreclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT chrisjohnson thepreclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT nicolawilsher thepreclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT vanessamartins preclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT georgeward preclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT tomokosmyth preclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT mikereader preclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT giannichessari preclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT chrisjohnson preclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy AT nicolawilsher preclinicalpharmacokineticsoftolinapantadualciap1xiapantagonistwithinvivoefficacy |