Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach

Zhang, Zhichao; Song, Ting; Li, Xiangqian; Wu, Zhi‐Yong; Feng, Yingang; Xie, Feibo; Liu, Chengwu; Qin, Jianquan; Chen, Hongbo

doi:10.1016/j.ejmech.2012.10.050

Cited by 27 publications

(8 citation statements)

References 31 publications

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“…As shown in Figure 2, screening of several fragments derived from the dissection of the unrevised S1 structure using a fluorescence polarization assay led to the identification of two novel hits: a 2-cyanoacetamide ( 7 )(Zhang, Song, et al, 2013), and a 2-hydroxynicotinonitrile ( 9 )(Zhang, Liu, et al, 2013). Synthetic elaboration of these molecules yielded compounds 8 , which is 6-fold more potent than S1, and 10 , which is equipotent to S1.…”

Section: S1 Derivativesmentioning

confidence: 99%

Small molecule Mcl-1 inhibitors for the treatment of cancer

Belmar

Fesik

2015

Pharmacology & Therapeutics

155

138

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The Bcl-2 family of proteins serves as primary regulators of apoptosis. Myeloid cell leukemia 1 (Mcl-1), a pro-survival member of the Bcl-2 family of proteins, is overexpressed and the Mcl-1 gene is amplified in many tumor types. Moreover, the overexpression of Mcl-1 is the cause of resistance to several chemotherapeutic agents. Thus, Mcl-1 is a promising cancer target. This review highlights the current progress on the discovery of small molecule Mcl-1 inhibitors.

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Section: S1 Derivativesmentioning

confidence: 99%

Small molecule Mcl-1 inhibitors for the treatment of cancer

Belmar

Fesik

2015

Pharmacology & Therapeutics

155

138

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“…Unless the demonstration that this activity is BAX/BAK-dependent, S1-derivative should be considered as a putative pan-BH3 mimetic. Other S1-derivatives were described as novel MCL-1 inhibitors [ 55 , 56 ].…”

Section: Inhibitors Of Prosurvival Bcl-2 Proteinsmentioning

confidence: 99%

New dimension in therapeutic targeting of BCL-2 family proteins

et al. 2015

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Proteins of the BCL-2 family control the mitochondrial pathway of apoptosis. Targeting these proteins proves to be an attractive strategy for anticancer therapy. The biological context is based on the fact that BH3-only members of the family are specific antagonists of prosurvival members. This prompted the identification of “BH3 mimetic” compounds. These small peptides or organic molecules indeed mimic the BH3 domain of BH3-only proteins: by selectively binding and antagonizing prosurvival proteins, they can induce apoptosis in malignant cells. Some small-molecule inhibitors of prosurvival proteins have already entered clinical trials in cancer patients and two of them have shown significant therapeutic effects. The latest developments in the field of targeting BCL-2 family proteins highlight several new antagonists of prosurvival proteins as well as direct activators of proapoptotic proteins. These compounds open up novel prospects for the development of BH3 mimetic anticancer drugs.

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“…Replacing the phenyl ring with more polar pyridyl rings (25,26) exhibited a more than 10-fold decreased potency. The thienyl ring (27) showed improved activity, while the bicyclic naphthyl ring (28) showed weaker activity compared to 16. The cycloalkane analogs are inactive (29,30), which suggested that the π-system of the rings attached to the sulfone linker was necessary for Mcl-1 inhibition (Table 3).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…27 Therefore, developing BH3 mimetic Mcl-1 inhibitors is a promising strategy for cancer therapy. 28 The large and shallow binding groove makes Mcl-1 intrinsically difficult to be targeted. 31 Several groups have developed peptide Mcl-1 inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability

Zhu

et al. 2021

J. Med. Chem.

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Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure–activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 μM) led to the discovery of the most potent compound 40 with high affinity (K d = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.

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Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach

Cited by 27 publications

References 31 publications

Small molecule Mcl-1 inhibitors for the treatment of cancer

Small molecule Mcl-1 inhibitors for the treatment of cancer

New dimension in therapeutic targeting of BCL-2 family proteins

Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability

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