19171-19-8

Basic information

• Product Name: Pomalidomide
• Synonyms: 3-Amino-N-(2,6-dioxo-3-piperidyl)phthalimide;4-Amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione;Pomalidomide;Pomalidomide(CC-4047);ActiMid;CC-4047;4-AMino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;1H-Isoindole-1,3(2H)-dione,4-aMino-2-(2,6-dioxo-3-piperidinyl)-
• CAS NO: 19171-19-8
• Molecular Formula: C₁₃H₁₁N₃O₄
• Molecular Weight: 273.24
• EINECS: 1592732-453-0
• Product Categories: Inhibitor;CC-4047;Inhibitors
• Mol File: 19171-19-8.mol

Chemical Properties

• Melting Point: 318.5 - 320.5°
• Boiling Point: 582.933 °C at 760 mmHg
• Flash Point: 306.347 °C
• Appearance: yellow/
• Density: 1.57 g/cm³
• Vapor Pressure: 1.41E-13mmHg at 25°C
• Refractive Index: 1.691
• Storage Temp.: 2-8°C
• Solubility: DMSO: ≥14mg/mL
• PKA: 10.75±0.40(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
• Merck: 14,135
• CAS DataBase Reference: Pomalidomide(CAS DataBase Reference)
• NIST Chemistry Reference: Pomalidomide(19171-19-8)
• EPA Substance Registry System: Pomalidomide(19171-19-8)

Safety Data

• WGK Germany: 3
• RTECS: NR3397905
• Hazardous Substances Data: 19171-19-8(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Pomalidomide is used as an antitumor agent for the treatment of multiple myeloma (MM) in patients with disease progression after receiving other cancer therapeutics. It has demonstrated potent inhibition of in vitro proliferation in various human MM cell lines, with an IC50 of approximately 10 nM. In mouse MM tumor models, daily doses of 50 mg/kg resulted in marked inhibition of tumor growth and complete regression in 3-6 weeks, outperforming thalidomide-treated controls at the same dose.
Used in Immunology:
Pomalidomide is used as an immunomodulator, with its effects including the modulation of immunity and inhibition of the cereblon protein. This makes it a valuable compound in the study and treatment of various immune-related conditions.
Used in Inflammation Management:
As an anti-inflammatory agent, pomalidomide is used to manage inflammation by inhibiting the production of TNF-α, a key pro-inflammatory cytokine. It has been shown to be a potent inhibitor of LPS-induced TNF-α release, with an IC50 of 13 nM.
Used in Drug Development:
Pomalidomide's chemical properties and biological activities make it a valuable compound for further drug development, particularly in the areas of oncology, immunology, and inflammation management. Its unique mechanism of action and improved toxicity profile compared to thalidomide make it an attractive candidate for the development of new therapeutics.

In vitro

Pomalidomide inhibits lipopolysaccharide (LPS) stimulated TNF-alpha release in human PBMC and in human whole blood with IC50 values of 13 nM and 25 nM, respectively. Pomalidomide inhibits the growth of T regulatory cells which is stimulated by IL-2 with an IC50 of ~1 μM. Treatment with Pomalidomide (6.4 nM-10 μM) increases the production of IL-2 in human peripheral blood T cells, and is slightly more potent in the CD4+ subset than in the CD8+ subset. Pomalidomide is significantly more potent than CC-5013 at elevating IL-2, IL-5, and IL-10 levels, but only slightly more potent than CC-5013 at elevating IFN-γ levels. Pomalidomide enhances SEE and Raji cells induced AP-1 transcriptional activity in Jurkat cells in a dose-dependent manner, with a maximal enhancement of 4-fold at 1 μM. Exposure of Raji cells to various concentrations of Pomalidomide (2.5-40 μg/mL) for 48 hours leads to a significant decrease in cell proliferation and DNA synthesis. There is a reduction of ~40% compared to vehicle-treated controls.

In vivo

Pomalidomide enhances the antitumor effect of rituximab against B-cell lymphomas in severe combined immunodeficient mice. Administration of Pomalidomide in combination with rituximab, gives the mice a median survival period of 74 days compared with 58 days of CC5013/rituximab treatment and 45 days of rituximab nonotherapy. The synergistic effect of Pomalidomide and rituximab can be completely abrogated by depletion of NK cells, supporting the proposal that NK cell expansion is one mechanism by which Pomalidomide may augment rituximab antitumor activity.

Originator

Celgene Corporation (United States)

Biochem/physiol Actions

Pomalidomide is an effective fetal hemoglobin (HbF) inducer that downregulates the key γ-globin repressors, SRY-box transcription factor 6 (SOX6), and BAF chromatin remodeling complex subunit (BCL11A).

Clinical Use

Treatment of multiple myeloma

Synthesis

First, condensation of commercially available 3-nitrophthalic anhydride (133) and L-glutamine in warm DMF gave nitrophthalimide 134. Although the authors from Celgene do not explicitly describe the racemization of the stereocenter derived from L-glutamine, scrambling of the stereocenter has been reported during this step under neutral conditions at elevated temperatures. Next, hydrogenative reduction of the nitro group furnished the anilinophthalimide 135, and this was followed by treatment with CDI in refluxing acetonitrile to secure the piperidone dione and ultimately furnish pomalidomide (XVIII) as the racemate in 87% overall yield from 134.

Drug interactions

Potentially hazardous interactions with other drugs Antidepressants: concentration increased by fluvoxamine.

Metabolism

Mainly metabolised in the liver by the cytochrome P450 isoenzymes CYP1A2 and CYP3A4, with CYP2C19 and CYP2D6 playing a minor role. Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy subjects, approximately 73% and 15% of the radioactive dose was eliminated in urine and faeces, respectively, with approximately 2% and 8% of the dosed radiocarbon eliminated as pomalidomide in urine and faeces.

References

1) Lopez-Girona?et al.?(2012),?Cereblon is direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide; Leukemia,?26?2326 2) Zhu?et al.?(2013),?Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma; Leukemia Lymphoma,?54?683 3) Donovan?et al.?(2018),?Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome; Elife,?7?e38430 4) Winter?et al.?(2015),?DRUG DEVELOPMENT. Phthalimide conjunction as a strategy for in vivo target protein degradation; Science,?348?1376 5) Lohbeck and Miller (2016),?Practical synthesis of a phthalimide-based Cereblon ligand to enable PROTAC development; Bioorg. Med. Chem. Lett.,?26?5260

InChI:InChI=1/C13H11N3O4/c14-7-3-1-2-6-10(7)13(20)16(12(6)19)8-4-5-9(17)15-11(8)18/h1-3,8H,4-5,14H2,(H,15,17,18)

Upstream product

• 24666-56-6 rac-α-aminoglutarimide hydrochloride 
• 6946-22-1 3-aminophthalic acid hydrochloride 
• 2635-64-5 2-(4-amino-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid 
• 19171-18-7 4-NT 
• 67-64-1 acetone 
• 530-62-1 1,1'-carbonyldiimidazole 
• 603-11-2 3-nitrophthalic acid 
• 6296-53-3 3-acetylaminophthalic anhydride 
• 444289-17-2 N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide 
• 641-70-3 3-nitrophthalic acid anhydride 
• 590365-46-1 (RS)-2,6-dioxopiperidin-3-yl-ammonium trifluoroacetate 
• 835616-60-9 2‐(2,6‐dioxopiperidin‐3‐yl)‐4‐fluoroisoindoline‐1,3‐dione 
• 652-39-1 3-fluorophthalic anhydride 
• 31140-42-8 (RS)-(2,6-dioxopiperidin-3-yl)carbamic acid tert-butyl ester 

Downstream Products

• 444288-17-9 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-nitro-benzamide 
• 444288-12-4 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide 
• 444288-06-6 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-methoxy-benzamide 
• 444287-79-0 N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]benzamide 
• 444287-99-4 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide 
• 444288-00-0 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-phenoxy-acetamide 
• 444288-20-4 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methoxy-benzamide 
• 444288-15-7 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-trifluoromethyl-benzamide 
• 444288-21-5 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-fluoro-benzamide 
• 444288-07-7 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-trifluoromethyl-benzamide 
• 444288-08-8 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-3-nitro-benzamide 
• 444287-82-5 N-(2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl)-2-phenylacetamide 
• 444287-95-0 2-benzyloxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-acetamide 
• 444287-84-7 2‐chloro‐N‐(2‐(2,6‐dioxopiperidin‐3‐yl)‐1,3‐dioxoisoindolin‐4‐yl)acetamide 

Relevant articles and documents

Effects of immunomodulatory derivatives of thalidomide (IMiDs) and their analogs on cell-differentiation, cyclooxygenase activity and angiogenesis

Various analogs of known immunomodulatory derivatives of thalidomide (1) (IMiDs: 3, 5) were synthesized, focusing on cell-differentiation-inducing, cyclooxygenase-inhibitory and anti-angiogenesis activities. Among the prepared compounds, NIDO-33 (14) showed cell differentiation-inducing activity on HL-60 cells and anti-angiogenic activity on human umbilical vein endothelial cells (HUVEC). AIDO-00 (7) also showed anti-angiogenic activity. NIDO-11 (8) showed an enhancing effect on all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation, and AIDO-30 (13) exhibited cyclooxygenase (COX)-inhibitory activity.

Chemical degradation of androgen receptor (Ar) using bicalutamide analog–thalidomide protacs

A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.

Rational Design and Synthesis of HSF1-PROTACs for Anticancer Drug Development

PROTACs employ the proteosome-mediated proteolysis via E3 ligase and recruit the natural protein degradation machinery to selectively degrade the cancerous proteins. Herein, we have designed and synthesized heterobifunctional small molecules that consist of different linkers tethering KRIBB11, a HSF1 inhibitor, with pomalidomide, a commonly used E3 ligase ligand for anticancer drug development.

PHOTO INDUCED CONTROL OF PROTEIN DESTRUCTION

By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin-proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were previously regarded as undruggable. The compounds described herein comprise a photolabile group on PROTACs, enabling the degradation of protein targets in a spatiotemporally controlled manner. By adding a photolabile caging group on ubiquitin recruiting moieties, light-inducible protein degradation was acheived. These opto-PROTACs display no activity in the dark, while restricted degradation can be induced at a specific time and rate by UVA-irradiation. Accordingly, these compounds provide light-controlled PROTACs and methods of using such compounds.

The tale of proteolysis targeting chimeras (PROTACs) for Leucine-Rich Repeat Kinase 2 (LRRK2)

Here we present the rational design and synthetic methodologies towards proteolysis-targeting chimeras (PROTACs) for the recently-emerged target leucine-rich repeat kinase 2 (LRRK2). Two highly potent, selective, brain-penetrating kinase inhibitors were selected, and their structure was appropriately modified to assemble a cereblon-targeting PROTAC. Biological data show strong kinase inhibition and the ability of the synthesized compounds to enter the cells. However, data regarding the degradation of the target protein are inconclusive. The reasons for the inefficient degradation of the target are further discussed.

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.

Synthesis process for continuously preparing pomalidomide by using microchannel reactors

The invention discloses a synthesis process for continuously preparing pomalidomide by using microchannel reactors. The synthesis process comprises the following steps tha (1) 3-nitrophthalic acid isdissolved in acetic anhydride, and a reaction is performed to obtain 3-nitrophthalic anhydride; (2) 3-nitrophthalic anhydride is dissolved in formic acid to prepare a homogeneous solution A; (3) 3-aminopiperidine-2,6-dione is dissolved in ammonium formate and formic acid to prepare a homogeneous solution B; (4) palladium on carbon and methanol are prepared into suspension C; (5) the homogeneous solution A and the homogeneous solution B are simultaneously pumped into a microstructured mixer I in a microchannel reaction device separately, and after mixing, the mixture is introduced into a microstructured reactor I; (6) the suspension C and an effluent from the microstructured reactor I are simultaneously pumped into a microstructured mixer II in the microchannel reaction device separately while the step (5) is carried out, and after mixing, the mixture is introduced into a microstructured reactor II; and (7) an effluent from the microstructured reactor II is collected to obtain pomalidomide.

CEREBLON BINDERS FOR THE DEGRADATION OF IKAROS

The present invention provides cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway along with their use in therapeutic applications as described herein.

Method for preparing 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds

The invention discloses a method for preparing 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds. The 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds are compounds shown as a formula (I) or pharmacologically acceptable salt of the compounds, solvate, polymorphic substances or stereoisomer, and a molecular structural formula of the compounds shown as the formula (I) is shown. The method includes carrying out hydrolysis reaction on compounds shown as a formula (II) in solvents under the condition of the presence of acid or alkali. A molecular structural formula of the compounds shown as the formula (JJ) is shown. The method has the advantages that the compounds shown as the formula (II) are high in solubility and easy to hydrolyze, steps for carrying out reduction reaction onmetal catalysts, further purifying products and the like can be omitted, and accordingly the method includes simple preparation steps; the 3-amine-N-(2, 6-dioxo-3-piperidyl)-phthalimide compounds which are products are high in yield and purity, and the method is suitable for large-scale industrial production.

Selective degradation of CDK6 by a palbociclib based PROTAC

Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.