Discovery of 3( S )-thiomethyl pyrrolidine ERK inhibitors for oncology

Boga, Sobhana Babu; Alhassan, Abdul-Basit; Cooper, Alan; Doll, Ronald J.; Shih, Neng‐Yang; Shipps, Gerald W.; Deng, Yongqi; Zhu, Haiyuan; Yang, Nan; Sun, Robert; Zhu, Liang; Desai, Jagdish; Patel, Mehul; Muppalla, Kiran; Gao, Xiaolei; Wang, James; Yao, Xin; Kelly, Joseph M.; Gudipati, Subrahmanyam; Paliwal, Sunil; Tsui, Hon‐Chung; Wang, Tong; Sherborne, Bradley S.; Xiao, Li; Hruza, Alan; Buevich, Alexei V.; Zhang, Li‐Kang; Hesk, David; Samatar, Ahmed A.; Carr, Donna; Long, Brian J.; Black, Stuart; Dayananth, Priya; Windsor, William; Kirschmeier, Paul T.; Bishop, Robert

doi:10.1016/j.bmcl.2018.04.063

Cited by 12 publications

(7 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…in the Red Sea, and Aegyptolidines A and B, from the fungus Aspergillus aegyptiacus [15], are known for their cytotoxic activity against several tumor cell lines [16]. The cytotoxic effects of pyrrolidine derivatives are exerted through various mechanisms, including cell cycle arrest [17,18], the induction of apoptosis and the modulation of various signaling pathways, among others [19,20]. Tumor cells exhibit high migration rates, leading to invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Tridecylpyrrolidine-Diol Derivative-Induced Apoptosis In Vitro

Nosálová

Kešeľáková

Kello

et al. 2023

IJMS

View full text Add to dashboard Cite

Despite the decreasing trend in mortality from colorectal cancer, this disease still remains the third most common cause of death from cancer. In the present study, we investigated the antiproliferative and pro-apoptotic effects of (2S,3S,4R)-2-tridecylpyrrolidine-3,4-diol hydrochloride on colon cancer cells (Caco-2 and HCT116). The antiproliferative effect and IC50 values were determined by the MTT and BrdU assays. Flow cytometry, qRT-PCR and Western blot were used to study the cellular and molecular mechanisms involved in the induction of apoptotic pathways. Colon cancer cell migration was monitored by the scratch assay. Concentration-dependent cytotoxic and antiproliferative effects on both cell lines, with IC50 values of 3.2 ± 0.1 μmol/L (MTT) vs. 6.46 ± 2.84 μmol/L (BrdU) for HCT116 and 2.17 ± 1.5 μmol/L (MTT) vs. 1.59 ± 0.72 μmol/L (BrdU), for Caco-2 were observed. The results showed that tridecylpyrrolidine-induced apoptosis was associated with the externalization of phosphatidylserine, reduced mitochondrial membrane potential (MMP) accompanied by the activation of casp-3/7, the cleavage of PARP and casp-8, the overexpression of TNF-α and FasL and the dysregulation of Bcl-2 family proteins. Inhibition of the migration of treated cells across the wound area was detected. Taken together, our data show that the anticancer effects of tridecylpyrrolidine analogues in colon cancer cells are mediated by antiproliferative activity, the induction of both extrinsic and intrinsic apoptotic pathways and the inhibition of cell migration.

show abstract

Section: Introductionmentioning

confidence: 99%

Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Tridecylpyrrolidine-Diol Derivative-Induced Apoptosis In Vitro

Nosálová

Kešeľáková

Kello

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Systematic introduction of steric hindrance groups at the 3-position of the pyrrolidine led to the discovery of 3( S )-thiomethyl pyrrolidine analog 7 (Figure ). This group vastly improved the PK (rat/dog AUC PK @10 mpk = 26/17 μM·h; rat/dog F % = 70/75, see ref for detailed structure–activity relationship (SAR) analysis) but with the loss of 2–3-fold cell potency when compared to PoC compound 5 . Herein we report further optimization of the lead 7 to which led to the discovery of a clinical candidate MK-8353, a highly potent and selective ERK1/2 inhibitor with good oral bioavailability across multiple preclinical species.…”

mentioning

confidence: 99%

“…Interestingly, the sulfone methyl pyrrolidine analog of compound 20 gave compound 22 , and the opposite enantiomer 3( R )-thiomethoxy of compound 20 gave compound 23 . Both compounds were shown to be weaker in ERK1/2 potency, illustrating the importance of a stereospecific structural requirement for this class of inhibitors for optimal potency …”

mentioning

confidence: 99%

“…Crystal structure of compound 5 and other related molecules in this series revealed that the pyrimidine group in the right-hand side (RHS) forms a key π−π interaction with Tyr-62 of the ERK protein. 12,13 The nature of the linker connecting the pyrimidine to the center core is critical for optimal binding as it orients the pyrimidine to pick up the π−π interaction with Tyr-62. We began SAR scrutinizing the piperidine-ene (double bond oxidation, a potential liability) on the RHS of the molecule 7 while holding the p-fluorophenyl indazole on the LHS constant, and the results are summarized in Table 1.…”

mentioning

confidence: 99%

“…This limited SAR illustrated that the piperidine-ene phenyl pyrimidine construction of the RHS of the molecule 7 was optimal in maintaining the ERK potency with improved PK. 12 The full profile of the clinical compound MK-8353 is depicted in Figure 3. MK-8353 is a potent and selective inhibitor of both active and inactive ERK1 and ERK2 kinases (IC 50 = 20 and 7 nM, respectively).…”

mentioning

confidence: 99%

See 2 more Smart Citations

MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology

Boga

Deng

Zhu

et al. 2018

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound ) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3()-thiomethyl pyrrolidine analog . Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate suitable for twice daily oral dosing as a potential new cancer therapeutic.

show abstract

One‐Pot Regioselective γ‐Trifluoromethylthiolation and γ‐Methylthiolation of Enals

Banoun,

Henault,

Magnier

et al. 2024

Eur J Org Chem

View full text Add to dashboard Cite

show abstract

Discovery of 3( S )-thiomethyl pyrrolidine ERK inhibitors for oncology

Cited by 12 publications

References 15 publications

Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Tridecylpyrrolidine-Diol Derivative-Induced Apoptosis In Vitro

Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Tridecylpyrrolidine-Diol Derivative-Induced Apoptosis In Vitro

MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology

One‐Pot Regioselective γ‐Trifluoromethylthiolation and γ‐Methylthiolation of Enals

Contact Info

Product

Resources

About