Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer

Lee, Min Ho; Christov, Plamen P.; Shaw, Subrata; Tarr, James C.; Zhao, Bin; Veerasamy, Nagarathanam; Jeon, Kyu Ok; Mills, Jonathan J.; Bian, Zhiguo; Sensintaffar, John; Arnold, Allison L.; Fogarty, Stuart A.; Perry, Evan; Ramsey, Haley E.; Cook, Rebecca S.; Hollingshead, Melinda G.; Millin, Myrtle Davis; Lee, Kyung Min; Koss, Brian; Budhraja, Amit; Opferman, Joseph T.; Kim, Kwang‐Ho; Arteaga, Carlos L.; Moore, William; Olejniczak, Edward T.; Savona, Michael R.; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.8b01991

Cited by 48 publications

(36 citation statements)

References 49 publications

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“…Ongoing efforts in the Fesik lab recently led to the synthesis of compound 42. The development of this substance used structure-based design and several rounds of optimization starting from tricyclic diazepinones [ 148 ]. Compound 42 halted tumor growth and was well tolerated at doses up to 100 mg per kg in xenograft models of MM and TNBC.…”

Section: Targeting Of Mcl-1 With Small Molecule Inhibitorsmentioning

confidence: 99%

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

et al. 2020

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Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.

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Section: Targeting Of Mcl-1 With Small Molecule Inhibitorsmentioning

confidence: 99%

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

et al. 2020

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“…The further modifications of this molecule is being made to improve the efficacy and bioavailability. Another analog has been made (compound 42), which bound to Mcl-1 with picomolar affinity (Ki = 70–300 pM) in order to displace Bim ( Lee et al, 2019 ). Compound 42 showed in vivo growth inhibition in xenograft models of MM and AML ( Lee et al, 2019 ).…”

Section: Development Of Selective Mcl-1 Inhibitorsmentioning

confidence: 99%

Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma

et al. 2021

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Multiple myeloma (MM) is a plasma cells neoplasm. The overexpression of Bcl-2 family proteins, particularly myeloid cell leukemia 1 (Mcl-1), plays a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis of MM. Thus, inhibition of the Mcl-1 protein considered as a therapeutic strategy to kill the myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. This review presents the critical role of Mcl-1 in the progression of MM, the most prominent BH3 mimetic and semi-BH3 mimetic that selectively inhibit Mcl-1, and could be used as single agent or combined with existing therapies.

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“…71 As shown in Figure 7, 40 possessed high Mcl-1 binding affinity with a K d of 0.23 nM, whereas no binding was observed against Bcl-2, Bcl-xL, Bcl-w, and Bcl2A1 (K d ≥ 10,000 In Vitro Anticancer Effects. After confirming the Mcl-1targeting ability in vitro, 27, 40, 41, 42, 43, and 44 were then tested for their antiproliferative activities against the tumor cell lines sensitive to Mcl-1 inhibitors (H929, MV4-11, SK-BR-3, and NCI-H23) 53,67,72 and the insensitive K562 cell line 49,53 through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colourimetric (MTT) assay. A1210477 and AZD5991 were selected as positive controls.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…43,44 In 2013, Fesik's team discovered an indole-based Mcl-1 inhibitor 2 by using the fragment merging method. 45 Further modifications 46−48 led to VU661013 (3) 49 with an ideal in vivo antitumor efficacy. 50 In 2015, AbbVie identified A1210477 (4) as an indole-based Mcl-1 inhibitor, 51,52 which is widely used as an in vitro chemical tool.…”

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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Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer

Cited by 48 publications

References 49 publications

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma

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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