Subscriber access provided by TULANE UNIVERSITY
Article
Discovery of Potent, Efficient and Selective Inhibitors of Phosphoinositide 3-Kinase # Through a Deconstruction and Regrowth Approach. Nick Barton, Maire A. Convery, Anthony W.J. Cooper, Kenneth David Down, Nicole Hamblin, Graham Inglis, Simon Peace, James E. Rowedder, Paul Rowland, Jonathan A Taylor, and Natalie Wellaway J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01556 • Publication Date (Web): 11 Dec 2018 Downloaded from http://pubs.acs.org on December 11, 2018
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of Medicinal Chemistry
Discovery of Potent, Efficient and Selective Inhibitors of Phosphoinositide 3‑Kinase δ Through a Deconstruction and Regrowth Approach.
Nick Barton, Maire Convery, Anthony W. J. Cooper, Kenneth Down*, J. Nicole Hamblin$, Graham Inglis, Simon Peace, James Rowedder, Paul Rowland, Jonathan A. Taylor and Natalie Wellaway. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, SG1 2NY, Stevenage, UK
Abstract A deconstruction of previously reported PI3Kδ inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ which was exploited to deliver a potent, efficient and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure. Introduction Phosphoinositide 3‑kinase δ (PI3Kδ) and the closely related isoforms PI3Kα, β and γ are class 1 lipid kinases, which catalyse the phosphorylation of phosphatidylinositol 4,5-bisphosphate to produce the key signalling molecule phosphatidylinositol 3,4,5-triphosphate, which in turn triggers a series of downstream biological events that affect cell growth, chemotaxis, differentiation, proliferation and survival1-5. The PI3Kα and β isoforms are ubiquitously expressed in all tissues and knock-out mice are embryonically lethal, whereas PI3Kδ and γ are predominantly expressed in leukocytes and mutagenic mice are viable with a phenotype consistent with immunological effects on B-cells, T-cells, and neutrophils, making them a target for the treatment of inflammatory conditions, such as asthma and COPD6-8. Many selective PI3Kδ inhibitors have been reported9-10, predominantly for oncology indications (for example Idelalisib11 (fig 1.)), although AM-8508 (fig. 1) was reported by Amgen as a potential treatment for inflammatory diseases12, leniolisib was progressed by Novartis into phase III trials for the treatment of activated PI3K delta syndrome13 and UCB have progressed seletalisib into clinical trials for patients with primary Sjogren’s syndrome14. We previously reported15 the discovery of highly potent PI3Kδ inhibitors nemiralisib, 1 and GSK2292767, 2 (fig. 1) for the treatment of respiratory indications via inhalation. Both these compounds are highly selective for PI3Kδ (≥ 1000-fold) with ideal properties for inhaled delivery (low bioavailability and moderate to high clearance) and are progressing through clinical trials16-19. In this
ACS Paragon Plus Environment
Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
communication, we describe the successful discovery of selective leads for PI3Kδ with different chemical starting points compared to inhaled clinical compounds 1 and 2, achieved via a deconstruction and regrowth approach. F
O
N
N N
N NH
NH N
N
N
N
N
F N
N
N
HN N N
NH2
Idelalisib
O N
F
N
N H
O F
AM-8508
leniolisib
O N
Cl
N N
N N N N+ F3C O-
NH N
N
N
HN
N H
N seletalisib
O
O
nemiralisib, 1
O H N S O O
N N H N 2
Figure 1. Selected PI3Kδ inhibitors. Results and Discussion We recently reported a lead series developed from an initial small, focussed array20 and herein we describe a broader approach leading to the discovery of a further lead series. A key focus in this exploration was to identify PI3K isoform selectivity differences such that subsequent lead optimisation studies would be better placed to deliver highly selective compounds. The binding modes of compounds 1 and 2, which had been determined based on homology modelling and later confirmed by crystallography15, indicated that the indole/pyridine sulfonamide group occupied the affinity pocket region of the kinase, the indazole made the key interaction with the “hinge” region and the oxazole/alkyl amine group accessed a region of the kinase known to impart selectivity for PI3Kδ over the other isoforms21. A deconstruction of compounds 1 and 2 to compounds 3-5 (Table 1) was performed to enable better understanding of the minimum pharmacophore required for potency. The oxadiazole in compound 5 was chosen in place of the oxazole primarily for ease of synthesis and, with a pendant morpholine substituent, was previously shown to have no impact on PI3K potency15.
ACS Paragon Plus Environment
Page 2 of 30
Page 3 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Journal of Medicinal Chemistry
pIC50 Compound Structure
PI3Kδ (LE)
PI3Kα
PI3Kβ
PI3Kγ
9.9*
5.3ab
5.8a
5.2c
10.1*
6.4
5.6
6.5
5.1 (0.39)
