The preclinical pharmacokinetics of Tolinapant-A dual cIAP1/XIAP antagonist with in vivo efficacy.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-12-01 DOI:10.1002/prp2.70030
Vanessa Martins, George Ward, Tomoko Smyth, Mike Reader, Gianni Chessari, Chris Johnson, Nicola Wilsher
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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.

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Tolinapant--具有体内疗效的 cIAP1/XIAP 双拮抗剂的临床前药代动力学。
AT-IAP(1-{6-[(4-氟苯基)甲基]-3,3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基}-2-[(2R,5R)-5-甲基-2-{[(3R)-3-甲基吗啉-4-基]甲基}哌嗪-1-基]乙烷-1-酮)被鉴定为 cIAP1/XIAP 蛋白的新型强效非丙氨酸小分子双重抑制剂。在临床前物种中对 AT-IAP 进行了评估,结果表明其在啮齿类动物中具有良好的生物利用度,在 MDA-MB-231 小鼠异种移植模型中口服 30 mg/kg 具有疗效。经鉴定,AT-IAP 的主要代谢途径由 CYP3A 驱动,因此在非人灵长类动物 (NHP) 研究中,由于等效 CYP3A 的表达相对较高,口服暴露量较低。AT-IAP 代谢物鉴定研究确定了吗啉或哌嗪分子的开环。通过大量的优化工作,加入羟甲基增加了极性,从而鉴定出了tolinapant(1-(6-[(4-氟苯基)甲基]-5-(羟甲基)-3、3-二甲基-1H,2H,3H-吡咯并[3,2-b]吡啶-1-基)-2-[(2 R,5 R)-5-甲基-2-([(3R)-3-甲基吗啉-4-基]甲基)哌嗪-1-基]乙-1-酮)的 CYP3A 代谢降低。托利奈潘在啮齿动物和 NHP 中的口服生物利用度为 12-34%,剂量为 5 毫克/千克。口服剂量为 5-75 毫克/千克时,在 NHP 中观察到非线性药代动力学。在 A375 小鼠异种移植模型中,5 至 20 毫克/千克剂量范围内的药效学调节和疗效得到了证实。通过降低 cIAP 1 蛋白水平衡量的靶向参与在 NHP 代替组织中得到了证实,并应用于托利那泛 1/2 期临床试验的靶向活性评估。
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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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