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Acuplanin

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40px-Terminal.png This article, Acuplanin, was written by RelentlessRecusant. Please do not edit this fiction without the writer's permission.
Acuplanin1

The chemical structure of Acuplanin, in its sodium salt suspension form.

Acuplanin Concept 1

Outline of integrative pharmacogenetics that led to the design of the dual kinase specificity purine library that generated RR8234.

Acuplanin Concept 2

Outline of high-throughput screening paradigm and forward chemical genetics used to used to identify RR8234 as a lead hit.

Acuplanin Concept 3

Outline of various techniques to validate the biological target of the small-molecule probe.

"Well, you know what they say. If you can't pronounce the ingredients, don't take it."
―Anonymous Phade Technology Industry competitor[Src]


Acuplanin is the marketed name of an anti-diabetic drug released by Acumen Science Laboratories and marketed by the 2560s. It is the first effacious and safe pharmacological treatment for Type 1 Diabetes that is approved by the UNSC Medical Corps. Acuplanin, also known as small molecule compound RR823490, has an IUPAC name of sodium (Z)-3-bromo-4-(2-carbamoyl-6-(1-(4-((4,4-dichlorocyclopent-1-enyl)(phenyl)methyl)benzoyloxy)-6-(methyl(oxo)ammoniooxy)-5-(4-methylcyclohexylsulfonyl)-4-(trifluoromethyl)-hex-1-en-2-yl)-9-(3-hydroxyphenyl)-9H-purin-8-yl)cyclopentanolate.

Acuplanin is a high-specificity multitargeted polypharmacological, and is the first known pharmacologically-active small molecule to target transcription factors.

Concept

Its genesis began with an intense pharmacogenetics program led by Beah Schore and the Department of Experimental Biology for the definition of a new chemical space and the expansion of the chemical universe to target a combinatorial location on the three-dimensional protein biological universe. A well-known bioactive small-molecule chemical library of the 2,6,8,9-tetraheterocycle-9H-purines underwent non-randomized templated organic augumentation to generate an expanded library of synthetic purines designed to likely have polypharmacological capability. This library underwent high-throughput screening of multiple human cell lines to determine if any family members demonstrated any notable biological activity.

Hit Confirmation

It was originally discovered as small molecule RR8234 (sodium 3-bromo-4-(2-carbamoyl-6-(cyclopenta-1,3,-dienyl)-9-(3-hydroxyphenyl)-9H-purin-8-yl)cyclopentanolate), a member of an inorganically-synthesized chemical library of 2,6,8,9-tetraalkyl-9H-purines as a polypharmacological dually-targeted specific kinase activator. Integrative high-content imaging of a library of pancreatic β-cells with fluorescently-labeled kianses was performed and Akt/PKB and CaMKIV, two protein kinases integral in pancreatic β-cell, were found to be novel interactants with RR8234. A kinome activity screen across the human kinome revealed weak and nonspecific activity against other kinases, confirming that RR8234 was a specific agent with potential pharmacological benefit. RR8234 was thus defined as a progenitor of a new chemical space that targeted two structurally-unrelated kinases, and was believed to have two novel active sites that potentiated the activity of these two kinases.

Lead Optimization

In silico lead optimization was then performed to augument RR8234's activity, and optimization was done through computer modelling and in vitro phenotypic high-throughput β-cell cultures.

While inorganic optimization identified several optimized products with increased solubility and potentially increased temporal kinetics, surprisingly, organic optimization with an N-methyl-N-oxo-O-(4,4,4,-trifluoro-2-(4-methylcyclohexylsulfonyl)butyl)hydroxylammonium side chain was shown to significantly impact β-cell phenotype in vitro; this optimized compound was known as RR823490. It was later identified that addition of this electron-accepting organic / inorganic chain led to increased polypharmacological activity, specifically transcription factor inhibitory capability. Affinity chromatography was performed and it was found that RR823490 was an ATP-independent competitor for nuclear transcription factor FOXO1, an important factor involved in β-cell physiology and diabetes pathophysiology. Kinome re-screening revealed that organic augumentation did not significantly effect activity on a kinome-wide scale, and in vitro high-throughput protein-based screening was done and it was found that the novel molecule was fairly specific for FOXO1, with little affinity for other FOXA or FOXO family members.

While RR8234, under Lipinski's Rule of Five, was likely to be an orally-applicable agent, the optimized product, RR823490, was determined to have inefficient gastrointestinal absorption for oral application, and that it would have to be intravenously applied, significantly complicating clinical usage, although the sodium salt formulation would increase venous solubility and pharmacoavailability. RR823490, marketed under "Acuplanin", underwent UNSC Medical Corps clinical trials for safety, efficacy, and efficiency, and although there was extremely light and rare neurotoxicity, interestingly, treated patients, under a pharmacoviligance program, were found to have increased spatial and procedural memory, likely a side-effect of CamKIV activation. While this led to moral questions about the administration of the drug, the high-benefit / low-risk situation of Type 1 Diabetes patients led to Acuplanin's near-immediate approval.

Conclusions

Since its release, Acuplanin has become an Acumen trademark, and its cure for Type 1 Diabetes has launched Acumen into the forefront of the public spotlight, despite its intravenous application and neurological side-effects.

While the exact mechanism of action demonstrated by Acuplanin is currently unknown, certain Acumen scientists tentatively believe that it may act as a potentiator of a specific biological module; the FOXO1 system, and by dually augumenting Akt activity and inhibiting FOXO activity that it allows for the potentiation of the β-cell compensatory response to pre-diabetic insulin resistance, a phenomenon which is mediated by Ca+2/CamKIV. An immunological or vascular target of action has not been discounted.

Behind the Scenes

  • Acuplanin's small-molecule library designation, "RR823490", is named after the initials of this article's author, RelentlessRecusant ("RR").
  • The complex organic and inorganic chemistry used to create Acuplanin's chemical structure was named by ChemBioDraw Ultra 11.0, a chemical program.
  • While the exact chemical structure of Acuplanin is not known to have any real-world phenotypic effect, it is based on a true real-world chemical library, the 2,6,8,9-tetraalkyl-9H-purines, which has led to the creation of numerous real-world drugs, such as "Reversine" and "Purmorphamine".
  • All chemical biology techniques, methodologies, and theories described in this article are factually-accurate and are used in real academic and corporate pharmacology in drug design.

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