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

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

doi:10.1021/acsmedchemlett.8b00220

Cited by 37 publications

(28 citation statements)

References 15 publications

(24 reference statements)

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“…In order to improve the pharmacokinetics of SCH772984, another indazole-pyrrolidine derivative, named MK-8353 (formerly, Compound 7, SCH900353, PubChem CID: 58282870) was developed; it displayed good oral bioavailability across multiple species, with an IC 50 in the low nM range, and no cross-inhibition of MEK1/2. The pharmacokinetic performances were improved over compound 5 by a careful structure-based drug design in which a 3(S)-thiomethyl substitution of the pyrrolidine core was inserted to retard amide metabolism [239]. Dose, schedule, and activity has been evaluated in the phase-I MK-8353-001 study (NCT01358331), which enrolled 26 patients affected by metastatic melanoma, colorectal cancer, or other solid tumors.…”

Section: Erk Inhibitors In the Treatment Of Melanomamentioning

confidence: 99%

Targeting the ERK Signaling Pathway in Melanoma

Savoia

Fava

Casoni

et al. 2019

IJMS

131

107

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The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

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Section: Erk Inhibitors In the Treatment Of Melanomamentioning

confidence: 99%

Targeting the ERK Signaling Pathway in Melanoma

Savoia

Fava

Casoni

et al. 2019

IJMS

131

107

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“…Babu Boga et al [ 70 ] developed a series of novel 3(S)-thiomethyl pyrrolidine-1 H -indazole derivatives aiming to identify new and safe compounds as ERK inhibitors for treatment of cancer. Among all the tested compounds, compound 119 displayed excellent potency, high ERK 1/2 selectivity and dual mechanisms of action inhibition (IC 50 = 20 and 7 nM, respectively) ( Figure 26 ).…”

Section: Biological Applications Of Indazole Derivativesmentioning

confidence: 99%

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

2018

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Indazole-containing derivatives represent one of the most important heterocycles in drug molecules. Diversely substituted indazole derivatives bear a variety of functional groups and display versatile biological activities; hence, they have gained considerable attention in the field of medicinal chemistry. This review aims to summarize the recent advances in various methods for the synthesis of indazole derivatives. The current developments in the biological activities of indazole-based compounds are also presented.

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“…On the other hand, inhibition of ERK, the last kinase of the cascade, has been aroused as a promising alternative for treating RAS overactivation. Compounds like the preclinical SCH-772984 or its improved version MK-8353 bind to ERK1/2 promoting its inactivation by avoiding its phosphorylation by MEK [137][138][139]. Both inhibitors decrease cell proliferation in preclinical assays, but did not generate antitumour responses in clinical trials [138].…”

Section: Targeting Ras Downstream Effectorsmentioning

confidence: 99%

Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance

Río-Vilariño

Puerto‐Nevado

García‐Foncillas

et al. 2021

Cancers

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Colorectal cancer remains among the cancers with the highest incidence, prevalence, and mortality worldwide. Although the development of targeted therapies against the EGFR and VEGFR membrane receptors has considerably improved survival in these patients, the appearance of resistance means that their success is still limited. Overactivation of several members of the Ras-GTPase family is one of the main actors in both tumour progression and the lack of response to cytotoxic and targeted therapies. This fact has led many resources to be devoted over the last decades to the development of targeted therapies against these proteins. However, they have not been as successful as expected in their move to the clinic so far. In this review, we will analyse the role of these Ras-GTPases in the emergence and development of colorectal cancer and their relationship with resistance to targeted therapies, as well as the status and new advances in the design of targeted therapies against these proteins and their possible clinical implications.

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

Cited by 37 publications

References 15 publications

Targeting the ERK Signaling Pathway in Melanoma

Targeting the ERK Signaling Pathway in Melanoma

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance

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