Skip to main content

New Drug Approvals 2011 - Pt. XXIX (ruxolitinib phosphate) (Jakafi ™)

ATC Code: L01XE18

On November 16th 2011, the FDA approved ruxolitinib phosphate (Tradename:Jakafi™ Research Code: INCB-018424), a JAK1/JAK2 inhibitor for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

Myelofibrosis is a disorder of the bone marrow, in which the marrow is replaced by scar (fibrous) tissue. Scarring of the bone marrow reduces its ability to blood cells, and can lead to anemia, bleeding problems, and a higher risk of infections due to reduced white blood cells. It is also associated with engorgement of organs suchs as the spleen and liver. Primary myelofibrosis may develop to secondary myelofibrosis - including leukemia and lymphoma. Myelofibrosis is associated with dysregulated Janus kinases JAK1 and JAK2, and some with a somatic mutation in JAK2 (JAK2V617F) (OMIM). JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines.

JAK1 (Uniprot:P23458) and JAK2 (Uniprot:O60674) are tyrosine protein kinases and members of the Janus kinase subfamily, where all members of the family contain two tandem protein kinase domains (PFAM:PF00069), one of which is catalytically active and one believed to be inactive. JAK1 and JAK2 are 43% identical by sequence and both have the 3D structure of their kinase domain determined (see e.g. PDBe:3EYH and PDBe:3Q32 for JAK1 and JAK2 respectively). Ruxolitinib is the first approved targeted JAK inhibitor, with several others in mid to late-stage clinical development (including CYT-387, GLPG-0634, INCB-28050, ONX-0803, NS-018, pacritinib (SB-1518), AZD-1480, BMS-911543, LS-104, XL-019, TG-101348, tofacitinib (CP-690550), VX-509, R-348, WHI-P131 and oclacitinib (PF-03394197) (veterinary applications)) - note these show a broad range of selectivity against the three known JAK subtypes.
Ruxolitinib (IUPAC: (R)-3-(4-(7H-pyrrolo[2,3­ d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate; (Standard InCHI key: HFNKQEVNSGCOJV-OAHLLOKOSA-N) has a molecular weight of 404.36, an AlogP of 2.88 and complies with all components of Lipinski's rule of 5.

Ruxolitinib is administered orally as the phosphate salt as tablets and dosed according to platelet count (hence the large range of dosage forms). Each tablet contains ruxolitinib phosphate equivalent to 5 mg, 10 mg, 15 mg, 20 mg and 25 mg of ruxolitinib free base. The Tmax for Ruxolitinib is 1-2 hours post dosing, with exposure (Cmax and AUC) linear over a dose range of 5mg to 200mg. Oral absorption is in excess of 95%. The volume of distribution is 53-65 L, with plasma protein binding in excess of 97%. Ruxolitinib is predominantly metabolized by CYP3A4, with the two primary metabolites displaying weaker, but still significant pharmacological activity against their specific targets. Administration of ruxolitinib with ketoconazole, a potent CYP3A4 inhibitor, prolongs the half life of ruxolitinib from 3.7 to 6.0 hours, increases the Cmax to 33% and the AUC to 91%. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole.

The license holder for Jakafi is Incyte, and the full prescribing information can be found here.


Unknown said…
Thanks for the post it prompted me to do some ChemSpider curation and deposition. However, as I looked at the post and the data, there is some confusion about Ruxolitinib and Jakafi. While they are related they are not exactly the same, but in the post this is not always clear.


Unknown said…
Actually, as soon as I posted that last comment I realised that there is another serious error in the post, and as a result in the ChemSpider links that I posted. The image that is in the post is the correct enantiomer (R), however the ChEMBL article and standard InChIkey are for the S-enantiomer.

The correct ChemSpider links are,


jpo said…
Hi, Thanks Dave. You are right.

The post failed to discriminate between the dosed salt (ruxolitinib phosphate) and the active compound form (ruxolitinib). I've reworded this.

More interesting though is that the original ChEMBL structure came from the paper and the structure is correct as drawn in the primary literature, since this is the only version currently in ChEMBL, the wrong enantiomer was tagged. So it is an example of an error in the literature being propagated. It's quite interesting, that the paper itself is about a different series, and the Incyte compound is listed as prior art, and we know from some error benchmarking in ChEMBL, that chemists drawing someone else's compound is a common source of errors.

So we'll fix this, and many thanks. Community curation at it's best!

Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site: .  Please see ChEMBL_29 release notes for full details of all changes in this release: New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no