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
• Article Data: 50

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

Description

Pomalidomide, also known as CC4047, is a 4-amino analog of thalidomide, an aromatic amine that is substituted at position 4 on the isoindole ring system by an amino group. It is a potent inhibitor of TNF-α production and serves as an anti-inflammatory and antitumor agent. Pomalidomide is a second-generation immunomodulator and a thalidomide analog with enhanced potency and an improved toxicity profile. It exerts its effects by modulating immunity, inhibiting angiogenesis, interfering with the bone/tumor microenvironment, and inhibiting the cereblon protein. Pomalidomide is a yellow solid and is marketed under the brand name Pomalyst.

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

• 19171-18-7 4-NT 
• 641-70-3 3-nitrophthalic acid anhydride 
• 2650-64-8 Cbz-L-Gln 
• 24666-56-6 rac-α-aminoglutarimide hydrochloride 
• 24666-55-5 3-(benzyloxycarbonyl)-amino-2,6-dioxopiperidine 
• 6946-22-1 3-aminophthalic acid hydrochloride 
• 2635-64-5 2-(4-amino-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid 
• 67-64-1 acetone 
• 530-62-1 1,1'-carbonyldiimidazole 
• 590365-46-1 (RS)-2,6-dioxopiperidin-3-yl-ammonium trifluoroacetate 
• 603-11-2 3-nitrophthalic acid 
• 340020-02-2 ethyl 4-amino-1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate 
• 2353-44-8 (+/-)-α-aminoglutarimide 

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 
• 444288-14-6 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoro-benzamide 
• 444288-19-1 N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methylsulfanyl-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 
• 444288-06-6 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 
• 444288-15-7 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 

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.

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.

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.