Pomalidomide: A new IMiD with remarkable activity in both multiple myeloma and myelofibrosis

Lacy, Martha Q.; Rajkumar, S. Vincent

doi:10.1002/ajh.21610

Cited by 18 publications

(13 citation statements)

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“…Thalidomide, pomalidomide, and lenalidomide, collectively known as immunomodulatory drugs (IMiDs), have been used to treat multiple myeloma for many years. [1][2][3][4] For the majority of this time, the molecular mechanism of action was unknown, rendering attempts to explore the structure-activity relationships challenging. [5,6] In recent years, the elucidation of the unique mechanism of action of these compounds has caused ar esurgence of interest in IMiDs.…”

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confidence: 99%

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

et al. 2018

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The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure-activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure-degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

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confidence: 99%

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

et al. 2018

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“…Lenalidomide is currently in use for the treatment of MM and myelodysplastic syndrome in combination with dexamethasone as second line therapy [49,50]. Pomalidomide, a third generation thalidomide analog, has been tested to treat MM and yielded promising results when combined with dexamethasone [51]. Side effects of lenalidomide and pomalidomide are neutropenia, fatigue and anemia [44,46].…”

Section: Thalidomide and Analoguesmentioning

confidence: 98%

Inhibition of Tumor Angiogenesis by Antibodies, Synthetic Small Molecules and Natural Products

Wahl¹,

Oswald²,

Tretzel³

et al. 2011

CMC

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Cancer remains one of the major causes of death worldwide. The switch to pathological angiogenesis is a key process in the promotion of cancer and consequently provides several new and promising targets to anticancer therapy. Thus, antagonizing angiogenesis cuts off the tumor's oxygen and nutrition supply. This review focuses on angiogenesis inhibitors as option for cancer treatment. Modes of action, adverse effects, mechanisms of resistance as well as new developments are highlighted. One approach in angiogenesis inhibition is intermitting the further VEGF (vascular endothelial growth factor) signal pathway with monoclonal antibodies. Bevacizumab is a highly specific recombinant humanized monoclonal IgG antibody targeting VEGF-A. An efficient antitumor therapy demands more specific antibodies that affect other signal molecules besides VEGF-A, which is in the focus of current research. In addition to antagonizing VEGF, there are also small molecules that inhibit receptor tyrosine kinases (RTKs). Many RTK inhibitors have been described, which exhibit different specificity profiles. The question, whether highly specific antagonists are necessary remains open, because other affected RTKs may also represent growth factor receptors that are essential for tumor growth. Therefore their inhibition may also contribute to anticancer activity. Secondary plant metabolites represent templates for the development of new small molecules. The identification of new drugs from plants has a long and successful history. There is convincing evidence for the beneficial effect of phytochemicals on cancer-related pathways, particularly with regard to anti-angiogenesis. Plant phenolics are the most important category of phytochemicals, including flavanoids. Prominent phytochemicals affecting different pathways of angiogenesis are green tea polyphenols (epigallocatechin gallate) and soy bean isoflavones (genistein).

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“…Its primary target has been identified to be cereblon (CRBN), which forms an E3 ligase complex with DDB1 and Cul4A that is important for limb development, and binding of thalidomide to this complex appears to be the mechanism for the teratogenic effects in embryonic development [55]. Two optimized second-generation derivatives of thalidomide, lenalidomide and pomalidomide [56,57], are also used for MM by targeting CRBN and modulate its specificity as a substrate receptor, not by inhibition, rather by selective enhancement of the ubiquitination and degradation of Ikaros 1 and 3 (IKZF1 and IKZF3) zinc finger transcription factors [84]. A crystal structure of lenalidomide in complex with CBRN shows the binding mode and that it binds to the substrate b inding domain of CRBN and blocks ubiquitination [85][86][87].…”

Section: Thalidomide and Its Derivativesmentioning

confidence: 99%

Targeting Ubiquitination for Cancer Therapies

Morrow¹,

Lin

Sun

et al. 2015

Future Med. Chem.

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Ubiquitination, the structured degradation and turnover of cellular proteins, is regulated by the ubiquitin-proteasome system. Most proteins that are critical for cellular regulations and functions are targets of the process. Ubiquitination is comprised of a sequence of three enzymatic steps, and aberrations in the pathway can lead to tumor development and progression as observed in many cancer types. Recent evidence indicates that targeting the ubiquitin-proteasome system is effective for certain cancer treatment, but many more potential targets might have been previously overlooked. In this review, we will discuss the current state of small molecules that target various elements of ubiquitination. Special attention will be given to novel inhibitors of E3 ubiquitin ligases, especially those in the SCF family.Ubiquitination, a step in the nonlysosomal degradation of proteins, is a crucial post-translational modification in eukaryotic organisms. Rapid and timely degradation of transcriptional regulators and other proteins by the ubiquitin-proteasome system (UPS) regulates a wide variety of cellular processes [1]. Ubiquitination involves covalent attachment of ubiquitin, a small 8-kDa protein, to a substrate and results in recognition and shuttling of the substrate to the 26S proteasome complex for degradation [2]. It is important to note that the ubiquitination process combined with the proteasome complex step is also referred to as the ubiquitin-proteasome system (UPS) or ubiquitin proteasome pathway (UPP).The ubiquitination process is tightly controlled by three families of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and finally ubiquitin-protein enzymes (E3s). There exists two E1 enzymes with ubiquitin-activating capability: UBA1 being the primary E1 and the recently discovered UBA6 with unclear functions and uncharacterized regulations [3,4]. In contrast to the small number of E1s, there are approximately 40 E2s [5,6] and 500-1000 human E3 ligases, providing both specificity and versatility [7]. The three steps of the ubiquitination process (Figure 1) have been reviewed previously [8,9]. Briefly, the activation step requires binding of both ATP and ubiquitin and links the α-carboxyl group of the C-terminal glycine residue of ubiquitin to a cysteine residue on E1, and a thioester linkage is formed between the u biquitin and E1.Then the E2 binds to both activated ubiquitin and the E1 enzyme and thus transfers the ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. Finally, the E3 catalyzes the linking of ubiquitin to a lysine residue on the substrate. Repetitions of these sequential steps results in a long chains of ubiquitin (polyubiquitin) on the protein to be degraded, and the specific lysine residue on ubiquitin used for linking (e.g., K48, K63, etc.) results in different topologies [10]. Ubiquitination was originally described as a mechanism by which cells dispose of short-lived, damaged, or abnormal proteins, but more rece...

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Pomalidomide: A new IMiD with remarkable activity in both multiple myeloma and myelofibrosis

Cited by 18 publications

References 36 publications

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

Inhibition of Tumor Angiogenesis by Antibodies, Synthetic Small Molecules and Natural Products

Targeting Ubiquitination for Cancer Therapies

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