Travel Report 20th RSC-SCI Medicinal Chemistry Symposium (Cambridge, UK) 08-11 September, 2019

 Lynette Smyth (AbbVie, Germany) Novel, potent and selective 5-HT2C receptor agonists for the treatment of neurological disorders  Items: o 5-HT2C has been indicated in a number of different neurological diseases such as schizophrenia, bipolar disorder and depression and has the potential to be useful in the symptomatic treatment of Alzheimer’s and Parkinson’s disease. The 5-HT2C agonist Locaserin was approved for the treatment of obesity in 2012. It was however shown, at that time, to have poor functional selectivity for 5-HT2C over 5-HT2A and 5-HT2B, leading to a limited tolerated maximal dose. o Therefore, it was desired to investigate new classes of 5-HT2C agonists with improved selectivity.

 However, the project was terminated due to ‘’strategic’’ reasons.

- 1 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Jean Quancard (Novartis, Switzerland) One binder, two effects. Context dependent inhibition or rescue of MALT1 protease  Items: o MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation, making it an attractive target for the treatment of autoimmune diseases. In vivo potency was optimized by 1) reducing clearance with guidance from metabolism identification studies and 2) increasing potency in whole blood by masking a hydrogen bond through intramolecular interaction. However, a patient was identified with a homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. The same allosteric binder can inhibit the wild type enzyme or rescue the MALT1-W580S mutant enzyme. o This suggests that the same drug may be used to treat autoimmune diseases associated with MALT1 activation or to treat combined immunodeficiency in patients with a MALT1 deficiency.

- 2 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  James Crawford (Genentech, USA) Resetting the antibacterial arms race: LepB as a novel gram negative target  Items: o The arylomycins are a class of antibiotics initially isolated from a soil sample obtained in Cape Coast, Ghana. In this initial isolation, two families of closely related arylomycins, A and B, were identified. We identified the arylomycin class of macrocyclic lipopeptides as a promising starting point based on their inhibition of an essential signal peptidase (SPase) in both Gram-positive and –negative bacteria. Reviewing what was known of their activity, spectrum and resistance profile, we began by attempting to capture interactions lost as a result of the missing P1 residue and simultaneously adding functionality to covalently modify the SPase active site serine. o The optimized arylomycins are unaffected by resistance evolved against therapeutics in current clinical use, and are highly active against 49 strains of multidrug resistant Gram-negative pathogens.

 Jodi T. Williams (Idorsia, Switzerland) The discovery of the selective orexin1 receptor antagonist (so1ra) act-539313 for the treatment of anxiety disorders  Items: o The neuropeptides orexin A (OX-A) and orexin b (OX-B) are synthesized by a small number of neurons in the hypothalamus. Orexin producing neurons project widely to key areas of the brain and are predominantly involved in the control of wakefulness and in the regulation of food intake, reward, addictive behaviors and stress. The OX neuropeptides mediate their effect by stimulating two distinct G-protein coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) that are co-located or selectively located in specific brain areas implying differentiated roles. Antagonism of the OX2 receptor is required to induce sleep, but selective antagonism of the OX1 receptor does not affect sleep. The OX1 receptor is selectively expressed in the bed nucleus of the stria terminalis, amygdala, cingulate cortex and locus coeruleus which paly are role in panic and anxiety. o Both dual orexin receptor antagonists (DORAs) and selective orexin-2 receptor antagonists (SO2RAs) have been shown to promote sleep in rodents and humans.

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 ACT-539313 is currently being prepared for Phase 2.

 Brock T. Shireman (Janssen, USA) Discovery and disclosure of JNJ-61393215, a selective orexin-1 receptor antagonist  Items: o Same as above.

 U-shape required for all selective OX1 receptor antagonists.

- 4 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Tim Harrison (ALMAC, UK) Ventures in new target space: drugging the DUBs  Items: o Deubiquitinating enzymes (DUBs) are proteases that catalyze the de-ubiquitination of protein substrates and as such offer an alternative way to regulate protein homeostasis. Furthermore, since ubiquitination also controls a plethora of regulatory functions beyond direct degradation, inhibition of DUBs provides additional opportunities to manipulate critical cellular processes. o As a result of this dual role in protein degradation and signaling, as well as their increasing linkage to the etiology of numerous pathological conditions including cancer, inflammation and neurodegeneration, DUBs have emerged as a new and attractive target class for the development of First-in-Class medicines with high therapeutic impact.

 Ubiquitin-specific-processing protease 7 (USP7), also known as ubiquitin carboxyl- terminal hydrolase 7 or herpesvirus-associated ubiquitin-specific protease (HAUSP), is an enzyme that in humans is encoded by the USP7 gene.

 Fang Gao (Biogen, USA) The investigation of small molecule inhibitors of PLD for the treatment of ALS  Items: o Phospholipase D (PLD) is an enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule phosphatidic acid and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression and is proposed to play a role in neurodegenerative disorders, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). o Studies at Biogen have demonstrated that knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS.

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 Michael E. Prime (Evotec, UK) Imaging mutant huntingtin aggregates: Development of potential PET ligands  Items: o Huntington’s disease (HD) is a rare (prevalence is 1 in 10000 worldwide), fatal, autosomal dominant inherited disease caused by CAG repeat expansion in the huntingtin (HTT) gene, which results in an expanded polyglutamine (polyQ) tract in the mutant huntingtin protein (mHTT). Clinical manifestations of the disease include motor and cognitive impairment, psychiatric disturbances, as well as metabolic abnormalities, with disease onset typically occurring between the ages of 30 and 50, and death 15 to 20 years after onset. Aggregates of mHTT form in brain cells and can be observed by post-mortem analysis. o It is not clear if mHTT aggregates are neuroprotective or neurodegenerative and this question is an area of much controversy and research. There are currently no tools to detect mHTT in vivo.

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 All binding data were obtained using synthetic mHTT fibrils. In addition, CHDI- 00485180 showed binding to human HD post-mortem tissue.  FIH evaluation of novel mutant huntingtin PET radioligands [¹¹C]CHDI-00485180-R and [¹¹C]CHDI-00485626. Start Date: 2020-02-01; Completion Date: 2022-02-01

 Michael D. Shultz (Novartis, USA) Do we need to change the definition of hit-, lead- and drug-like properties?  Items: o Two decades have passed since the rule of five ushered in the concept of "drug-like" properties. Attempts to quantify, correlate, and categorize molecules based on Ro5 parameters evolved into the introduction of efficiency metrics with far reaching consequences in decision making by industry leaders and scientists seeking to discover new medicines. Examination of oral drug parameters approved before and after the original Ro5 analysis demonstrates that some parameters such as clogP and HBD remained constant while the cutoffs for parameters such as molecular weight and HBA have increased substantially over the past 20 years. The time dependent increase in the molecular weight of oral drugs during the past 20 years provides compelling evidence to disprove the hypothesis that molecular weight is a "drug-like" property. This analysis does not validate parameters that have not changed as being "drug-like" but instead calls into question the entire hypothesis that "drug-like" properties exist.  For more details see Shultz, M. D. Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs. J Med Chem. 2019, 62, 1701-1714.

- 7 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  David J. Edmonds (Pfizer, USA) A potent, orally bioavailable small molecule agonist of the GLP-1 receptor  Items: o Glucagon-like peptide-1 (GLP-1) receptor agonists comprise a growing class of agents that deliver unprecedented efficacy in diabetes. Members of the class are also approved or under development for obesity and the class shows further promise for the treatment of non-alcoholic steatohepatitis (NASH). GLP-1 is 30 amino acid peptide hormone that activates the GLP-1 receptor, a class B GPCR that is particularly challenging to stimulate with small molecules. To date, all approved agents are large peptide drugs that are administered by injection, negatively impacting both patient experience and uptake of these highly effective medicines.

- 8 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Richard L. Mackman (Gilead, USA) Discovery of GS-9688, a selective toll-like receptor 8 agonist for Hepatitis B cure  Items: o Chronic hepatitis B (CHB) is one of the principal cause of chronic liver disease, cirrhosis and hepatocellular carcinoma, and is characterized by a dysfunctional immune response. Stimulation of the host innate and adaptive immune response, for example, activation of natural killer cells, stimulation of myeloid dendritic cells, and enhancement of HBV-specific T-cells, could lead to an effective new ‘’curative’’ treatment of CHB. o Toll-like receptors (TLR) are a family of pattern recognition receptors that recognize pathogen-associated molecular fragments and trigger innate and adaptive immune responses. In myeloid cells, TLR8 activation generates and array of cytokines, including IL-12, IL-18, TNF-α, and published data has shown TLR8 induced cytokines can rescue the antiviral function of exhausted HBV-specific CD8+ T cells and suppress HBV replication in vitro.

- 9 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Ylva E. Bozikis (Cancer Therapeutics CRC, Australia) A potent and selective PRMT5 inhibitor for the potential treatment of acute myeloid leukaemia  Items: o Protein arginine methylation, catalyzed by a family of arginine methyl transferases, has emerged as one of the most common post-translational modifications. Protein arginine methyltransferase 5 (PRMT5) – a member of this family – catalyzes the formation of symmetrical dimethylarginines using SAM (5-adenosylmethionine) as a co-factor on histones and non-histone substrates. o Through increased methylation of epigenetic and non-epigenetic targets, the aberrant activity of PRMT5 has been associated with many pro-tumorigenic cellular changes, such as increased levels of protein synthesis, dysregulation of cell cycle, cellular adaptation to hypoxic conditions and suppression of normal cell death pathways.

 Maria Isabel Castellote Alvaro (GSK, Spain) Discovery of GSK701, a novel orally effective preclinical candidate for the treatment of malaria  Items: o Malaria remains a major global health problem. In 2017 alone, 219 million cases of malaria were reported, and more than 435000 deaths occurred. Since 2010, emerging resistance to current front-line ACT’s (Artemisinin Combination Therapies) has been detected in endemic countries. o Therefore, there is an urgent need to replace those drugs compromised by resistance, as well as identifying potential novel therapies that offer significant advantages over the current standard of care.

- 10 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Joshi Ramanjulu (GSK, USA) Discovery and development of novel amidobenzimidazole (ABZI) STING agonists as cancer therapeutics  Items: o Stimulator of Interferon Genes (STING) is an ER resident receptor that propagates innate immune sensing of cytosolic pathogen-derived and self-DNA. The development of compounds that modulates STING has recently been the focus of intense research for the treatment of cancer, infectious disease as well as vaccine adjuvants. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides (CDN), which mimic STING’s endogenous ligand cGAMP, that have progressed into clinical trials in patients with solid accessible tumors amendable to intratumoral delivery. o We report the discovery of a novel small molecule non-CDN STING agonist which functions as a systemically efficacious treatment of tumors in mice.

o The antitumor activity of DMXAA has been linked to its ability to induce a variety of cytokines and chemokines, including TNF-a, IP-10, IL-6 and RANTES. o DMXAA is also a potent inducer of IFN-ß. Despite significant preclinical promise, DMXAA failed human clinical trials. Recent studies have demonstrated that DMXAA targets the STING pathway, and this in a mouse-specific manner. DMXAA has no effect on human STING. A single point mutation (S162A) located within the cyclic- dinucleotide-binding site of human STING has been identified that renders it sensitive to DMXAA.

 Systemic administration of diABZI STING agonist to immunocompetent mice with established syngeneic colon tumors (CT-26) elicits remarkable anti-tumor activity with complete and durable regression of tumors.

- 11 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Martin H. Bolli (Idorsia, Switzerland) The discovery of Cenerimod – a selective S1P1 receptor modulator in phase II clinical trials in SLE  Items: o Systemic Lupus Erythematosus (SLE) is a chronic progressive autoimmune disease of unknown cause. While in SLE any organ of the body may be affected, the skin, joints, blood cells, lungs, brain, heart and kidneys are most commonly damaged by the autoimmune reaction. By sequestering lymphocytes from circulation, Sphingosine-1- phosphate receptor 1 (S1P1) receptor modulators have been shown to constitute a promising treatment option for a number of autoimmune diseases.

 Nathan Fuller (Rodin Therapeutics, USA) Discovery of RDN-929, an HDAC-CoREST complex-selective inhibitor that promotes pro-synaptic integrity for therapeutic treatment of synaptopathies  Items: o Synaptic dysfunction is a pathological feature in many neurodegenerative disorders, including Alzheimer’s disease, and synaptic loss correlates closely with cognitive decline. Histone deacetylases (HDACs) are involved in chromatin remodeling and gene expression, and have been shown to regulate synaptogenesis and synaptic plasticity, thus providing an attractive drug discovery target for promoting synaptic growth and function. o Historically, HDAC inhibitor compounds with pro-synaptic effects have been plagued by known HDAC dose-limiting hematological toxicities, precluding their application to treating chronic neurologic conditions. We have identified a series of novel HDAC inhibitor compounds that selectively inhibits the HDAC-CoREST complex while minimizing hematological side effects.

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 Class 1 HDAC's are upregulated in AD and PD.  Synaptic vesicle glycoprotein 2A (SV2A) is expressed ubiquitously in neurons of the central nervous system and can be used for monitoring synaptic density in neurodegenerative diseases.  Rodin Therapeutics is a 100% virtual company and relies on 8 CRO’s to perform the work. The synthesis CRO is Syngene.

 Christopher Brain (Novartis, Switzerland) & Steven Howard (Astex, UK) The discovery of Kisqali® (ribociclib), a CDK4/6 inhibitor for the treatment of breast cancer  Items: o Cyclin-dependent kinases (CDKs) 4 and 6 are enzymes that have been shown to promote cell division and multiplication in both normal and cancer cells. Many cancer cells have shown abnormalities that increase the activity of CDK, leading to the inactivation of certain tumor suppressor genes. The CDK4/6 pathway plays a central role in controlling cell cycle progression and is dysfunctional in a number of human cancers.

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 Ribociclib was approved by the US FDA in March 2017 and the European Medicines Agency in August 2017 for use in combination with an aromatase inhibitor (such as letrozole) to treat HR-positive, HER2-negative advanced or metastatic breast cancers.

 Stefan Gradl (Bayer, Germany) Discovery of BAY2402234 by phenotypic screening: A human Dihydroorotate Dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies  Items: o DHODH is a key enzyme in the biosynthesis of pyrimidines and recent studies have renewed interest in this old anti-cancer target. Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients.

 For more details see Christian, S. et al Leukemia 2019; https://doi.org/10.1038/s41375-019-0461-5

- 14 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Junliang Hao (Eli Lilly, USA) Discovery of LY3154207, a potent and selective dopamine receptor D1 positve allosteric modulator for the treatment of Parkinson’s disease dementia  Items: o The dopamine receptor D1 subtype (D1) is the most abundant dopamine receptor in the central nervous system, and plays an important role in motor activity, reward, and higher cognitive functions. Catechol-based D1 orthosteric agonists have been extensively studied and are active in many clinically relevant neuropsychiatric disorder models in preclinical species. However, attempts to develop these agonists for clinical use have thus far been largely unsuccessful due to receptor desensitization, poor ADME/PK properties, and dose limiting side effects (e.g. hypotension, nausea).

 LY3154207 entered Phase 2 clinical studies for Parkinson’s disease dementia in Q4/2017 (PRESENCE).

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 Poster #: 7 Anna Cederbalk (University of Oxford, UK) TAOK 1 & 2 inhibitors in Alzheimer’s disease  Items: o Phosphorylation of tau is important for the regulation of tau-microtubule interactions but when hyperphosphorylated (an early event in AD and FTLD), tau-disassembles from the microtubule and ultimately leads to the formation of neuronal fibrillary tangles (NFT). Several kinases are known to be involved in the phosphorylation of tau.The kinases TAOK1 and TAOK2 phosphorylate tau on multiple residues, including the pathological sites S262 and S356.

 Poster #: 32 Michael M.-C. Lo (Merck, USA) Discovery and optimization of potent, bioavailable M4 positive allosteric modulators with a 2,3,6-trisubstituted pyridine core  Items: o There has been continuous interest in developing a compound that selectively activates the muscarinic acetylcholine receptor M4 over the other subtype receptors and avoids undesirable side effects attributed to poor subtype selectivity. We and others have investigated M4 positive allosteric modulators (PAMs), which potentiate the M4 response through binding to allosteric sites and impart better subtype selectivity through avoiding the highly conserved orthosteric acetylcholine site.

- 16 - H:\General\01-ACI\External Meetings & Reports\2019\SCI_RSC MedChem\Conference report  Poster #: 53 Carlos M. Martinez Viturro (Janssen, Spain) Discovery of a novel series of spirocycles as non-saccharide O-GlcNAcase (OGA) inhibitors for the treatment of Alzheimer’s disease (AD)  Items: o In AD pathogenesis, tau is hyperphosphorylated on serine and threonine residues, which is thought to be one of the underlying causes for its detachment from mircotubules and subsequent aggregation. O-GlcNAcylation (reversible modification of serine or threonine residues with N-acetyl-D-glucosamine) of tau in vitro lowers the speed and yield of aggregation and additionally, may compete with phosphorylation. o This may render tau less prone to detaching from microtubules and reduces aggregation into neurotoxic tangles which ultimately lead to neurotoxicity and neuronal death.

 Next step: In vivo PK/PD study.

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