OUR TARGETS

We focus on the “triad” of related disease areas: metabolic disorders, oncology and immunology, which share overlapping biological mechanisms that drive disease.

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Metabolic

Metabolic disease such as diabetes, obesity and fatty liver disease (including NASH) continues to represent a widespread and serious global health problem. There is a significant need for new strategies to treat many types of metabolic disorders. As the scientific community continues to learn about the underlying biological pathways that drive metabolic disease development and advancement, there are several areas of emerging interest that are focused on more targeted, selective treatment approaches.

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Immunology

Immunological disorders are characterized by immune system dysfunction and can be broadly classified into two categories: immunodeficiency disorders and autoimmune diseases. Immune deficiencies occur when the immune system does not function correctly, which results in increased susceptibility to infections. Autoimmune conditions are characterized by abnormal activation of the immune system that causes it to attack and damage the body’s own tissues. Numerous diseases are the result of underlying immunological dysfunction, and these include Crohn’s disease, multiple sclerosis, psoriasis, rheumatoid arthritis, lupus and irritable bowel syndrome, among others.

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Oncology

One in three people will get cancer in their lifetime, a disease where the body’s cells begin to divide without stopping and spread into surrounding tissues. This is an area where there have been major advances in therapies in recent decades, yet patients remain in profound need for new medicines.

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Immuno-oncology

Recognized as one of the most important breakthroughs in cancer treatment in the last decade, “immuno-oncology” describes the field of certain therapeutics that activate the immune system to combat cancer.

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Cancer Metabolism

Cancer cells use and process nutrients and energy in the body differently than healthy cells and tissue. Differences in those biological pathways can be targeted in drug development to selectively kill cancer cells while sparing healthy tissue.

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Immuno-metabolism

The immune system’s role in metabolic disease is profound; in certain cases an overactive immune system can cause or contribute to disease. By targeting cells in the immune system, a whole range of metabolic diseases from diabetes to NASH, to obesity and others can be addressed.

View Our Publications & Abstracts

TYK2

Tyk2 (tyrosine kinase 2) is an important signal-transduction kinase for key pro-inflammatory cytokine receptors, including IL-23, IL-12 and interferons α and β. As a result, Tyk2 is a key target for the treatment of several challenging auto-immune disorders, including rheumatoid arthritis, SLE (lupus), Crohn’s disease, psoriasis, multiple sclerosis and others. In addition, some cancers, like T-ALL, appear to be driven by Tyk2 hyper-activation and are responsive to Tyk2 inhibition.

Quick Facts:

  • Member of the Jak family of signaling kinases (Jak1, Jak2, Jak3, Tyk2)Striking human genetic association with multiple auto-immune disorders
  • Potential to replicate efficacy of Th17 biologics (anti-IL23, anti-IL17) with a small molecule drug
  • Not inhibited by “Jakinibs” (e.g. tofacitinib and others) at clinical doses
  • Catalytic activity regulated by allosteric site (i.e. JH2, pseudokinse)

Disease categories:

  • Oncology
  • Immunology

Nimbus Approach:

  • Potent allosteric inhibitors with marked Tyk2 functional selectivity (>1000x, vs. other Jaks)
  • Catalytic inhibitors with dissociation from Jak2 (anemia) and titratable inhibition of Jak1/3
View Nimbus Publications
& Abstracts

Further Reading:

  • Diogo, D. et al, TYK2 Protein-Coding Variants Protect Against Rheumatoid Arthritis And Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits (2015) 4: e0122271 journals.plos.org
  • Dendrou, C.A. et al, Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity (2016) 8:363-149 stm.sciencemag.org

sting

STING (stimulator of interferon genes) plays a key role in the activation of the innate immune system in response to viral infection and to cytosolic DNA in tumor cells. STING agonism (turning STING “on”) provokes anti-tumor responses in animal models of cancer, including checkpoint inhibitor-resistant (e.g. PD1) tumors. In contrast, STING antagonists (STING “off”) could have therapeutic potential in type-I interferonopathies, such as SLE (lupus), where STING drives exaggerated interferon responses.

Quick Facts:

  • Key member of cGAS-STING-TBK1 sensing mechanism for “inappropriate” cytosolic DNA
  • Activation leads to potent anti-tumor response
  • Inhibition blocks Type-I interferon formation

Disease categories:

  • Oncology
  • Immunology

Nimbus Approach:

  • Small molecules (not nucleotides or analogs) for true drug-like properties and potency
  • Building both agonists (oncology) and antagonists (inflammation)
View Nimbus Publications
& Abstracts

Further Reading:

  • Corrales, L. et al, Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity (2015) 11: 1018-30 www.cell.com
  • Chen, Q. et al, Regulation and Function of the cGAS-STING Pathway of Cytosolic DNA Sensing (2016) 10: 1142-9 www.nature.com

ACC

ACC (acetyl-CoA carboxylase) is a master regulator of fatty acid biosynthesis and oxidative degradation. It catalyzes the first committed step in the elongation of fatty acid precursors by converting acetyl-CoA to malonyl-CoA. ACC has long been a target for metabolic disorders like obesity and diabetes, but more recently for NASH (non-alcoholic steatohepatitis). Because of the key role that ACC plays in lipid biosynthesis for rapidly proliferating cells, inhibitors may also have utility in certain cancers (i.e. HCC, NSCLC, breast, prostate) and Th17-driven inflammatory disorders. Nimbus’ ACC program was acquired by Gilead in 2016.

Quick Facts:

  • Two isoforms: cytosolic ACC1 (fatty acid biosynthesis) and mitochondrial ACC2 (controls oxidative degradation)
  • Distinct allosteric site on BC domain (biotin carboxylase) and catalytic site on CT domain (carboxyl-transferase)
  • Most advanced compound (GS-0976) in Phase-2 for NASH

Disease categories:

  • Metabolic
  • Oncology
  • Immunology

Nimbus Approach:

  • High-potency allosteric inhibitors
  • Inhibit both ACC1 and ACC2 to attenuate FA synthesis and stimulate FA degradation
  • Tissue-targeting hepatotropic pharmacophores for liver diseases and broadly distributed compounds for other disorders
View Nimbus Publications
& Abstracts

Further Reading:

  • Harriman, G. et al, Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats (2016) 13:E1796-80 www.pnas.org
  • Svensson, R. et al, Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models (2016) 10:1108-1119 www.nature.com

IRAK4

IRAK4 (interleukin-1 receptor-associated kinase 4) is a signal transduction kinase that plays a well-validated role in mediating both adaptive and innate immune responses. It communicates the signals emanating from IL-1 and IL-18 receptors, as well as some TLRs (toll-like receptors) via the adapter protein MyD88. Inhibitors of IRAK4 have therapeutic potential for several inflammatory disorders, including SLE (lupus), rheumatoid arthritis, IBD (inflammatory bowel disease) and gout. In addition, several B-cell malignancies are driven by MyD88 mutations and are responsive to IRAK4 inhibitors, including some that are hypo-responsive to Btk, Syk or PI3Kδ therapeutics. Nimbus’ IRAK4 program was exclusively licensed to Genentech in 2015.

Quick Facts:

  • Signal transduction kinase at crossroads of adaptive and innate immunity
  • Confers signal transduction from receptor: MyD88 to NFκB
  • Role in B-cell lymphomas with MyD88 mutations (Waldenströms and other ABC-DLBCLs)

Disease categories:

  • Oncology
  • Immunology

Nimbus Approach:

  • Historically intractable target resolved by Nimbus’ structural biology / computational chemistry approach
View Nimbus Publications
& Abstracts

Further Reading:

  • Kelly, P. et al, Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy (2015) 13:2189-201 jem.rupress.org
  • Netea, M. et al, Genetic variation in Toll-like receptors and disease susceptibility (2012) 6:535-42 www.nature.com

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