Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

Shah, Shrenik K.; He, Shuwen; Guo, Liangqin; Truong, Quang; Qi, Hongbo; Du, Wu; Lai, Zhong; Liu, Jian; Jian, Tianying; Hong, Qingmei; Dobbelaar, Peter H.; Ye, Zhixiong; Sherer, Edward C.; Feng, Zhe; Yu, Yang; Wong, Frederick; Samuel, Koppara; Madiera, Maria; Karanam, Bindhu V.; Reddy, Vijay Bhasker G.; Mitelman, Stan; Tong, Sharon; Chicchi, Gary G.; Tsao, Kwei-Lan; Trusca, Dorina; Feng, Yue; Wu, Margaret; Shao, Qing; Trujillo, María E.; Eiermann, George J.; Cai, Li; Pachanski, Michele; Fernandez, Guillermo; Nelson, Donald J.; Bunting, Patricia B.; Morissette, Pierre; Volksdorf, Sylvia; Kerr, Janet S.; Zhang, Bei B.; Howard, Andrew D.; Zhou, Yunping; Pasternak, Alexander; Nargund, Ravi P.; Hagmann, William K.

doi:10.1021/ml500514w

Cited by 21 publications

(14 citation statements)

References 12 publications

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“…This, however, remains untested. 11 The identity of the tandem AP[AS]CQ motif residues affecting CTS1 function in Sstr3-IC3 also remains unclear. The cysteines are very good candidates, as they are required for Sstr3-IC3 to bind the BBSome, a ciliary cargo adapter required for Sstr3 ciliary accumulation 30,35 .…”

Section: Discussionmentioning

confidence: 99%

Htr6 and Sstr3 ciliary targeting relies on both IC3 loops and C-terminal tails

Barbeito

Tachibana

Martin-Morales

et al. 2020

Preprint

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G protein-coupled receptors (GPCRs) are the most common pharmacological target in clinical practice. To perform their signaling functions, many GPCRs must accumulate at primary cilia, microtubule-based plasma membrane protrusions that work as cellular antennae. Despite their great importance, the molecular mechanisms underlying GPCR ciliary targeting remain poorly understood. Serotonin receptor 6 (Htr6) and somatostatin receptor 3 (Sstr3) are two brain-enriched ciliary GPCRs controlling cognition and involved in multiple pathologies such as Alzheimer's disease and cancer. We previously showed that the third intracellular loops (IC3s) of Htr6 and Sstr3 contain ciliary targeting sequences (CTSs) that are sufficient to confer ciliary localization to non-ciliary GPCRs. However, these CTSs are dispensable for the ciliary targeting of Htr6 and Sstr3 themselves, suggesting these GPCRs have additional CTSs. Herein, we show that the C-terminal tails of Htr6 and Sstr3 also contain CTSs, which act redundantly with those in the IC3s. Accordingly, simultaneous disruption of CTS1 (IC3) and CTS2 (C-terminal tail) abolishes ciliary targeting of both receptors. Mapping the individual residues required for Htr6 ciliary targeting reveals RKQ and LPG motifs critical for CTS1 and CTS2 function, respectively. In Sstr3, CTS1 function relies on the tandem AP[AS]CQ motifs and a subsequent arginine-rich stretch, whereas CTS2 operation requires the juxtamembrane residues. Furthermore, we shed light on the mechanisms of action of Htr6 CTSs by showing how they regulate binding to Tulp3 and Rabl2, two adapters needed for ciliary GPCR targeting. 3 (IC3s). This was first found for Sstr3 and Htr6 and was later extended to others like Mchr1, Gpr161, Mc4r or Npy2r 9,[20][21][22][23] .For Sstr3 and Htr6, their CTSs were discovered by generating chimeras between these ciliary GPCRs and their non-ciliary relatives Sstr5 and Htr7. After extensive analyses, replacing the IC3s of Sstr5 or Htr7 with those of Sstr3 or Htr6, respectively, was found to suffice for ciliary targeting of the nonciliary receptors. Furthermore, ciliary targeting of these chimeras was abolished by mutating to phenylalanine the first and last residues of Ax[AS]xQ motifs (hereafter referred to as A-Q motifs) present in the IC3s of both Sstr3 and Htr6 20 . In this study, another interesting observation was noted: the reverse pair of chimeras, in which the IC3s of Sstr3 and Htr6 were replaced by those of Sstr5 and Htr7, still accumulated in cilia, indicating that the newly discovered CTSs, albeit sufficient for ciliary targeting of non-ciliary receptors, were dispensable for ciliary targeting of Sstr3 and Htr6 themselves. This suggested, it was also noted, the presence of additional CTSs in these receptors 20 . A subsequent study confirmed that Htr6 IC3 is dispensable for its ciliary targeting 16 .Herein, we report the identification and characterization of those missing CTSs. We show that, for both Sstr3 and Htr6, ciliary targeting occurs as long as either IC3, CT, or both, are pre...

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Section: Discussionmentioning

confidence: 99%

Htr6 and Sstr3 ciliary targeting relies on both IC3 loops and C-terminal tails

Barbeito

Tachibana

Martin-Morales

et al. 2020

Preprint

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“…SST 3 agonists inhibit insulin release from INS-1 cells ( Mergler et al, 2008 ). At the systemic level, highly selective SST 3 antagonists such as MK-1421 or MK-4256 facilitate glucose-stimulated insulin secretion from pancreatic β -cells and block glucose excursion in wild-type, but not SST 3 KO mice ( Pasternak et al, 2012 ; Shah et al, 2015 ; He et al, 2016 ). This suggests that SST 3 antagonism represents a new potential mechanism for treating type 2 diabetes mellitus.…”

Section: Somatostatin Receptormentioning

confidence: 99%

“…Tetrahydro- β -carboline derivatives such as MK-1421 or MK-4256 are highly selective for SST 3 . They were shown to facilitate glucose-stimulated insulin secretion from pancreatic β -cells and block glucose excursion in rodents in vivo ( Pasternak et al, 2012 ; Shah et al, 2015 ; He et al, 2016 ). MK-4256 has been evaluated as a potential candidate for treatment of type 2 diabetes mellitus ( Fig.…”

Section: Somatostatin Receptormentioning

confidence: 99%

“…MK-4256 has been evaluated as a potential candidate for treatment of type 2 diabetes mellitus ( Fig. 14 ; Table 6 ) ( He et al, 2012 , 2016 ; Shah et al, 2015 ). However, development was discontinued due to adverse cardiovascular effects related to human ether-a-go-go–related gene off-target side effects ( He et al, 2014 ).…”

Section: Somatostatin Receptormentioning

confidence: 99%

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International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

et al. 2018

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Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

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“…More generally, arylated imidazoles are a fundamental scaffold of various drug-lead molecules. [12][13][14][15][16][17][18][19][20] The synthesis of N-heteroarylated imidazoles via C-H activation, however, has not been systematically studied.…”

Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed C–H Heteroarylation of 2,5-Disubstituted Imidazoles

Togo

Sohma

Kuninobu

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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We developed a palladium-catalyzed C-H N-heteroarylation of N-protected-2,5-disubstituted imidazoles at the C4position using N-heteroaryl halides as a coupling partner. Intensive reaction condition screening led us to identify fluorinated bathophenanthroline 7 as the optimum ligand for the palladium catalyst. This reaction will enhance lead optimization of drug candidates by facilitating the synthesis of heterobiaryl compounds containing an imidazole ring.

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Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

Cited by 21 publications

References 12 publications

Htr6 and Sstr3 ciliary targeting relies on both IC3 loops and C-terminal tails

Htr6 and Sstr3 ciliary targeting relies on both IC3 loops and C-terminal tails

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

Palladium-Catalyzed C–H Heteroarylation of 2,5-Disubstituted Imidazoles

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