6jid

Human MTHFD2 in complex with Compound 1Human MTHFD2 in complex with Compound 1

Structural highlights

6jid is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MTDC_HUMAN

Publication Abstract from PubMed

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD). DS44960156 would offer a good starting point for further optimization based on the following features: (1) unprecedented selectivity (>18-fold) for MTHFD2 over MTHFD1, (2) a molecular weight of less than 400, and (3) good ligand efficiency (LE).

Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.,Kawai J, Ota M, Ohki H, Toki T, Suzuki M, Shimada T, Matsui S, Inoue H, Sugihara C, Matsuhashi N, Matsui Y, Takaishi S, Nakayama K ACS Med Chem Lett. 2019 May 24;10(6):893-898. doi:, 10.1021/acsmedchemlett.9b00069. eCollection 2019 Jun 13. PMID:31223444^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kawai J, Ota M, Ohki H, Toki T, Suzuki M, Shimada T, Matsui S, Inoue H, Sugihara C, Matsuhashi N, Matsui Y, Takaishi S, Nakayama K. Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold. ACS Med Chem Lett. 2019 May 24;10(6):893-898. doi:, 10.1021/acsmedchemlett.9b00069. eCollection 2019 Jun 13. PMID:31223444 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00069

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Kawai J, Ota M, Ohki H, Toki T, Suzuki M, Shimada T, Matsui S, Inoue H, Sugihara C, Matsuhashi N, Matsui Y, Takaishi S, Nakayama K. Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold. ACS Med Chem Lett. 2019 May 24;10(6):893-898. doi:, 10.1021/acsmedchemlett.9b00069. eCollection 2019 Jun 13. PMID:31223444 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00069

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