Biotech's wellspring—a survey of the health of the private sector in 2014

Huggett, Brady

doi:10.1038/nbt.3218

Cited by 10 publications

(5 citation statements)

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“…[18][19][20][21][22][23] Accordingly, hIDO was identified as a key drug target in immuno-oncology. [24][25][26][27] In 2006, a second isoform of hIDO (human indoleamine 2,3 dioxygenase 2, referred to as hIDO2) was discovered in the human genome, 28,29 in addition to the original isoform (human indoleamine 2,3 dioxygenase 1, referred to as hIDO1 hereinafter). Like hIDO1, hIDO2 as well as hTDO were later found to be expressed in cancer cells, [30][31][32][33] where they play crucial roles in suppressing antitumor immunity.…”

Section: Introductionmentioning

confidence: 99%

“…Recently it was found that hIDO is expressed in the placenta and in cancer cells, , where the enzyme functions as an immunosuppressor by depleting Trp, the key nutrient required for T-cell activation and function, and by promoting the production of immunosuppressive kynurenine metabolites. − Accordingly, hIDO was identified as a key drug target in immuno-oncology. − In 2006, a second isoform of hIDO (human indoleamine 2,3 dioxygenase 2, referred to as hIDO2) was discovered in the human genome, , in addition to the original isoform (human indoleamine 2,3 dioxygenase 1, referred to as hIDO1 hereinafter). Like hIDO1, hIDO2 as well as hTDO were later found to be expressed in cancer cells, − where they play crucial roles in suppressing antitumor immunity.…”

Section: Introductionmentioning

confidence: 99%

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Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase

2019

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Indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are two of the only three heme-based dioxygenases in humans. They have recently been identified as key cancer immunotherapeutic drug targets. While structures of hIDO1 in complex with inhibitors have been documented, so far there are no structures of hTDO-inhibitor complexes available. Here we use PF-06840003 (IPD), a hIDO1-selective inhibitor in clinical trials, as a structural probe to elucidate inhibitor-selectivity in hIDO1 versus hTDO. Spectroscopic studies show that IPD exhibits 400fold higher inhibition activity toward hIDO1 with respect to hTDO. Crystallographic structures reveal that the binding pocket of IPD in the active site in hIDO1 is much more flexible as compared to that in hTDO, which offers a molecular explanation for the superior inhibition activity of IPD in hIDO1 with respect to hTDO. In addition to the IPD bound in the active site, a second IPD molecule was identified in an inhibitory site on the proximal side of the heme in hIDO1 and in an exosite that is ~40 Å away from the active site in hTDO. Taken together the data provide new insights into structure-based design of mono and dual inhibitors targeting hIDO1 and/or hTDO.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase

2019

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“…The majority of dietary Trp (∼95%) is metabolized to nicotinamide adenine dinucleotide (NAD) via the kynurenine (KYN) pathway. , The first and rate-limiting step of the KYN pathway, the dioxygenation of Trp to N -formylkynurenine (NFK), is catalyzed by human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO). In addition, to control Trp flux along the KYN pathway, hIDO1 and hTDO are involved in cancer immune escape via the Trp → KYN → AhR pathway. − Consequently, they have been considered as two important drug targets for cancer immunotherapy. − While the roles of hIDO1 and hTDO in cancer biology have been subject to extensive studies, molecular properties of the two enzymes remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Inhibition Mechanisms of Human Indoleamine 2,3 Dioxygenase 1

et al. 2018

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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) catalyze the same dioxygenation reaction of Trp to generate N-formyl kynurenine (NFK). They share high structural similarity, especially in the active site. However, hIDO1 possesses a unique inhibitory substrate binding site (Si) that is absent in hTDO. In addition, in hIDO1, the indoleamine group of the substrate Trp is H-bonded to S167 through a bridging water, while that in hTDO is directly H-bonded to H76. Here we show that Trp binding to the Si site or the mutation of S167 to histidine in hIDO1 retards its turnover activity and that the inhibited activity can be rescued by an effector, 3-indole ethanol (IDE). Kinetic studies reveal that the inhibited activity introduced by Trp binding to the Si site is a result of retarded recombination of the ferryl moiety with Trp epoxide to form NFK and that IDE reverses the effect by preventing Trp from binding to the Si site. In contrast, the abolished activity induced by the S167H mutation is primarily a result of ∼5000-fold reduction in the O binding rate constant, possibly due to the blockage of a ligand delivery tunnel, and that IDE binding to the Si site reverses the effect by reopening the tunnel. The data offer new insights into structure-based design of hIDO1-selective inhibitors.

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“…Despite its relative infancy, it has successfully established itself as a billion-dollar industry [3, 6], which is projected to grow—supported by an increasing number of marketable products, fiscal investment, and strong M&A (merger and acquisition) activity [7]. In 2014 alone, venture capital investment into the biotech sector surpassed $9 billion (USD) [8] and transformed an industry historically plagued by overly exuberant investments and multibillion-dollar losses [9] into a stable and sustainable market that appears attractive for both future investment and long-term value.…”

Section: Review Backgroundmentioning

confidence: 99%

An assessment of the factors affecting the commercialization of cell-based therapeutics: a systematic review protocol

et al. 2017

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BackgroundCellular-based therapies represent a platform technology within the rapidly expanding field of regenerative medicine and are distinct from conventional therapeutics—offering a unique approach to managing what were once considered untreatable diseases. Despite a significant increase in basic science activity within the cell therapy arena, alongside a growing portfolio of cell therapy trials and promising investment, the translation of cellular-based therapeutics from “bench to bedside” remains challenging, and the number of industry products available for widespread clinical use remains comparatively low. This systematic review identifies unique intrinsic and extrinsic barriers in the cell-based therapy domain.Methods/designEight electronic databases will be searched, specifically Medline, EMBASE (OvidSP), BIOSIS & Web of Science, Cochrane Library & HEED, EconLit (ProQuest), WHOLIS WHO Library Database, PAIS International (ProQuest), and Scopus. Addition to this gray literature was searched by manually reviewing relevant work. All identified articles will be subjected for review by two authors who will decide whether or not each article passes our inclusion/exclusion criteria. Eligible papers will subsequently be reviewed, and key data extracted into a pre-designed data extraction scorecard. An assessment of the perceived impact of broad commercial barriers to the adoption of cell-based therapies will be conducted. These broad categories will include manufacturing, regulation and intellectual property, reimbursement, clinical trials, clinical adoption, ethics, and business models. This will inform further discussion in the review. There is no PROSPERO registration number.DiscussionThrough a systematic search and appraisal of available literature, this review will identify key challenges in the commercialization pathway of cellular-based therapeutics and highlights significant barriers impeding successful clinical adoption. This will aid in creating an adaptable, acceptable, and harmonized approach supported by apposite regulatory frameworks and pertinent expertise throughout the respective stages of the adoption cycle to facilitate the adoption of new products and technologies in the industry.Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-017-0517-4) contains supplementary material, which is available to authorized users.

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Biotech's wellspring—a survey of the health of the private sector in 2014

Cited by 10 publications

References 0 publications

Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase

Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase

Inhibition Mechanisms of Human Indoleamine 2,3 Dioxygenase 1

An assessment of the factors affecting the commercialization of cell-based therapeutics: a systematic review protocol

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