Congenital Adrenal Hyperplasia
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Biochemical pathways of adrenal steroidogenesis consist of three major routes that all start with cholesterol: mineralocorticoids (end product: aldosterone), glucocorticoids (end product: cortisol), and sex steroids (end product: testosterone) (Figure 52.1). Multiple proteins/enzymes are required for these biochemical pathways, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), 17α-hydroxylase/17,20-lyase (CYP17A1), cytochrome b5 (CYB5A), 21-hydroxylase (CYP21A2), 11β-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2), and 17β-hydroxysteroid dehydrogenase type 5 (AKR1C3) (Figure 52.1). Although mutations in the underlying genes encoding any of these proteins/enzymes may cause disruptions in steroidogenesis, potentially leading to CAH, those affecting 21 hydroxylase (P450c21), 11ß hydroxylase (P450c11β) and 17α-hydroxylase/17,20-lyase (P450c17), stand out most (Table 52.1). In fact, mutations in the CYP21A2 (6p21.3), CYP11B1 (8q24.3), and CYP17A1 (10q21-q22) genes encoding P450c21, P450c11β, and P450c17 account for approximately 90%, 5%, and 5% of CAH cases, respectively (Table 52.1) [7–10].
Genetic Engineering of Clostridial Strains for Cancer Therapy
Ananda M. Chakrabarty, Arsénio M. Fialho in Microbial Infections and Cancer Therapy, 2019
Nevertheless, the lack of an optimal NTR/prodrug combination was compounded when safety concerns around the use of CB1954 in humans were brought to light; a phase I study in cancer patients revealed dose-limiting diarrhea and hepatotoxicity, with subsequent toxicological studies confirming metabolism of the prodrug by endogenous human liver enzymes [80, 87]. Naturally, research also branched toward the identification of novel prodrugs that are either safer or a better match with candidate NTRs; these include dinitrobenzamide mustards, oxazino-acrinides, nitrobenzyl, and nitroheterocyclic carbamate prodrugs [78, 79]. A subset of these compounds has indeed demonstrated better binding and cytotoxic properties than CB1954 in combination with nfsB or other NTRs, as well as a more pronounced bystander effect. Most notable and clinically advanced among those is PR-104, a dinitrobenzamide mustard initially developed as a hypoxia-activated prodrug. PR-104 is also the only prodrug apart from CB1954 that has been tested in combination with an NTR-expressing clostridial strain; in fact, Liu et al. demonstrated that PR-104 in combination with an sNTR-expressing C. sporogenes strain was more efficient than CB1954 in generating a sustained tumor reduction in mice with SiHa xenografts, even at comparatively lower administered doses [40]. Unfortunately, findings from phase I/II clinical trials employing PR-104 have cast doubts on the clinical utility of this prodrug; dose-limiting myelotoxicity attributed to prodrug metabolism by the human aldo-keto reductase 1C3 (AKR1C3) as well as high levels of clearance were common shortcomings responsible for stalling the clinical implementation of PR-104, inside or outside CDEPT [82].
Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Maša Sinreih, Rebeka Jójárt, Zoltán Kele, Tomaž Büdefeld, Gábor Paragi, Erzsébet Mernyák, Tea Lanišnik Rižner
These structure–activity relationship studies also revealed that chlorine substitution of 13β-methyl-17-keto oestrones at C-2 and/or C-4 was required for AKR1C3 inhibition, with improvement for both at the same time (IC50: 1_2Cl,4Cl, 6.3 µM; Figure 4). With bromine substitution showing low inhibition of AKR1C3, all inhibition was lost with either no substitution or iodine substitution. For 13α-methyl-3-methoxy-17-keto-oestrones, bromine or chlorine substitution at C-2 and the larger halogens at C-4 (i.e. chlorine, iodine) were required for AKR1C3 inhibition, while this inhibition of AKR1C3 was almost completely lost when the 17-keto group was removed. Methylation of 3-hydroxy group greatly improved the potency of the AKR1C3 inhibition.
A comprehensive review of hormonal and biological therapies for endometriosis: latest developments
Published in Expert Opinion on Biological Therapy, 2019
Fabio Barra, Giovanni Grandi, Matteo Tantari, Carolina Scala, Fabio Facchinetti, Simone Ferrero
In the latest years, new targets, which may significantly contribute to the development of endometriosis, have been investigated. Among them, AKR1C3 encodes a member of the aldo/keto reductase superfamily, which, importantly, catalyzes the reduction and the oxidation of several PGs (PG-D2, PG-H2, and 9-α,11-β-PG-F2, respectively) [164]. Its expression seems to be reduced by the use of progestins [165]. An ongoing randomized, placebo-controlled, double-blind, the dose-response study is evaluating the efficacy and safety of different oral doses of BAY1128688 for treating patients with symptomatic disease over a 12-week treatment period (NCT03373422).
The possible role of methylglyoxal metabolism in cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Khalid O. Alfarouk, Saad S. Alqahtani, Saeed Alshahrani, Jakob Morgenstern, Claudiu T. Supuran, Stephan J. Reshkin
For AKR inhibitors, the Pharmacodiagnostics approach should be implemented for the rational use of selection for example, forAKR1B1 is inhibited by epalrestat94AKR1C1 is inhibited by 3-bromo-5-phenylsalicylic acid95.AKR1C3 is inhibited by cinnamic acid96,97.
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