Pipeline & Targets

Our diverse pipeline of novel small molecule candidates is being advanced with a deep understanding of the molecular drivers of disease, enabled by our unique expertise in structure-based drug discovery.

WRN
Selectively targeting a synthetic lethal dependency of microsatellite instable tumors
Discovery

Target Selection

WRN (Werner syndrome helicase) is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). WRN inhibitors are expected to induce synthetic lethality in MSI tumors due to the essential role of WRN helicase activity, as recently discovered in multiple CRISPR screens. The ability to readily identify MSI tumors enables a clear stratification path in the clinic.

Approach

We are enabling a protein structure-guided approach to the identification of both active-site and allosteric inhibitors of WRN DNA helicase activity. While precedence for pharmacological inhibition of helicase is limited, WRN is amenable to structural biology which provides a strong opportunity to develop agents for this important subset of solid tumors.

Breakthroughs by Design

Selective inhibitors of WRN have the potential to induce synthetic lethality as a treatment for tumors with MSI.

Further Reading

Chan, E.M. et al., WRN helicase is a synthetic lethal target in microsatellite unstable cancers (2019). Nature 568, 551-556

Behan, F.M. et al., Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens (2019). Nature 568, 511–516

Cbl-b
A negative regulator of anti-tumor immune responses as a target for immuno-oncology
Discovery

Target Selection

Cbl-b (Casitas B-cell lymphoma) is an E3 ubiquitin ligase that directs the degradation of proteins essential in signaling across a variety of immune cells. Cbl-b is a well-validated immuno-oncology target, given that Cbl-b knockout mice spontaneously reject tumors with enhanced T and NK cell responses, and Cbl-b deficient T cells can be activated in the absence of co-stimulatory signals.

Approach

We are pursuing a protein structure-guided approach to identify and optimize allosteric inhibitors of Cbl-b that block target phosphorylation and inhibit enzymatic activity of this E3 ubiquitin ligase.

Breakthroughs by Design

Cbl-b inhibitors will prevent Cbl-b dampening of immune responses to enhance anti-tumor immunity.

Further Reading

Lutz-Nicoladoni, C. et al., Modulation of immune cell functions by the E3 ligase Cbl-b (2015). Frontiers in Oncology 5, 58

Paolino, M. et al., Essential role of E3 ubiquitin ligase activity in Cbl-b–regulated T cell functions (2011).  Journal of Immunology 186, 2138-2147

CTPS1
Key enzyme in the pyrimidine synthesis pathway as a target for autoimmune disease and cancer
Discovery

Target Selection

CTPS1 (CTP synthase 1) is involved in the de novo synthesis of CTP, a precursor of DNA, RNA and phospholipids, all of which are essential for lymphocyte proliferation. CTPS1 levels are substantially upregulated following stimulation of T cells, and primary T cells deficient in CTPS1 do not proliferate in response to stimulation. Agents targeting DHODH, upstream in the pathway, are being developed for hematologic cancers; first-generation agents against DHODH have been used to treat rheumatologic diseases.

Approach

We are using structure-based and computational chemistry approaches to identify small molecules that are highly potent inhibitors of CTPS1 with selectivity over CTPS2.

Breakthroughs by Design

Selective inhibitors of CTPS1 attenuate lymphocyte proliferation and provide effective treatments for T cell-driven diseases.

Further Reading

Fairbanks L. et al., Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans (1995). J Biol. Chem 270, 29682-29689

Martin, E. et al., CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation (2014). Nature 510, 288–292

TYK2
Allosteric inhibition to address autoimmune disorders with compelling human genetics
Clinical

Target Selection

TYK2 (tyrosine kinase 2) is an important signal-transducing kinase that mediates immune signaling and is important in both adaptive and innate immune cells. The TYK2 protein catalyzes the phosphorylation and activation of STAT proteins downstream of several cytokine receptors, including the IL-23, IL-12 and type I interferon receptors. Human genetic studies have shown that mutations in TYK2 that reduce kinase activity and downstream signaling are protective in a large number of autoimmune and inflammatory diseases, including psoriasis. Inhibition of TYK2 is expected to impact psoriasis pathogenesis primarily through its effects on the IL-23/Th17/Th22 axis.

Approach

Utilizing unique and innovative structure-based drug design technologies, Nimbus rapidly designed highly selective, potent allosteric inhibitors against TYK2 with suitable pharmaceutical properties as potential therapeutics in inflammatory disorders. This allosteric interaction with the TYK2 JH2 pseudokinase domain results in highly selective inhibition of TYK2 kinase activity compared to the other homologous proteins in the Janus Kinase (JAK) family of non-receptor tyrosine kinases (JAK1, JAK2 and JAK3).

Breakthroughs by Design

The Nimbus TYK2 allosteric inhibitor possesses exceptional TYK2 functional selectivity and is currently under clinical development.

Partnership

In October 2017, Nimbus and Celgene entered a long-term strategic immunology alliance, which includes Nimbus’ TYK2 program. Under the terms of the agreement, Nimbus received an upfront payment and is eligible for potential downstream milestone payments if Celgene chooses to exercise its option to acquire the TYK2 program. Nimbus retains full control of research and development activities for the TYK2 program prior to the program’s option point.

HPK1
Key regulator of T cell, B cell and dendritic cell‑mediated immune responses
Preclinical

Target Selection

HPK1 (hematopoietic progenitor kinase 1) is an intracellular negative regulator of T cell proliferation and signaling and dendritic cell activation. HPK1 kinase-dead knock-in mice demonstrate increased CD8+ T cell function, increased cytokine secretion and robust anti-tumor immune responses even in an immunosuppressive tumor environment, making HPK1 a high-priority target in immuno-oncology.

Approach

We have taken a comprehensive approach combining structural biology, physics-based computational chemistry and medicinal chemistry to develop reversible, ATP-competitive HPK1 inhibitors that are highly potent and highly selective over other MAP4K and immune receptor kinases.

Breakthroughs by Design

Our HPK1 inhibitors activate primary T cells that are exposed to an immunosuppressive environment. They show excellent target engagement in vivo, and mediate significant tumor growth inhibition in syngeneic murine tumor models both as single agents and in combination with a checkpoint inhibitor.

Partnership

In July 2019, Nimbus and Celgene expanded their long-term strategic alliance to include Nimbus’ HPK1 program. Under the terms of the agreement, Celgene received an option to acquire the program up through a development inflection point. Nimbus will retain full control of research and development activities for the program prior to the program’s option point. Financial terms will remain undisclosed until Celgene exercises its option to acquire the program.

ACLY
Critical pathway in metabolic reprogramming for metabolic disorders and cancer
Discovery

Target Selection

ACLY (ATP citrate lyase) functions as a key metabolic node that governs fatty acid and sterol production and also connects metabolism to the epigenome through its key role in producing the metabolite acetyl-CoA. ACLY has long been considered a therapeutic target in metabolic diseases associated with dyslipidemia but recent insights provide additional rationale for targeting ACLY in cardiovascular disease and cancer.

Approach

We have developed a structure-guided approach to the identification and optimization of allosteric ACLY inhibitors through the generation of a full-length cryo-EM structure of the ACLY tetramer.

Breakthroughs by Design

Our inhibitors of ACLY suppress both cholesterol and fatty acid synthesis, supporting the development of ACLY inhibitors as a therapeutic approach for metabolic diseases.

Further Reading

Wei, J. et al., An allosteric mechanism for potent inhibition of human ATP-citrate lyase (2019). Nature 568, 566-570

Pinkosky, S.L. et al., Targeting ATP-citrate lyase in hyperlipidemia and metabolic disorders (2017). Trends in Molecular Medicine 23, 1047-1063

Wang, Q. et al., Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice (2009). Hepatology 49, 1166-1175

AMPKβ2
Canonical regulator of major cellular energy balance for a broad range of diseases
Discovery

Target Selection

AMPK (AMP-activated protein kinase) is a kinase that serves as a critical regulator of energy sensing and metabolic homeostasis in many tissues. Activation of AMPK in the liver, skeletal muscle and other tissues has profound impacts in metabolic disease models of NASH and diabetes, and small molecule activation of AMPK has long been recognized as a potential strategy to treat these and other metabolic disorders.

Approach

AMPK consists of a trimer comprised of α, β and γ subunits; two isoforms of β exist.  We are using structural biology combined with computational chemistry approaches to identify small molecules that activate the AMPKβ2-containing forms that are present at high levels in skeletal muscle and liver in humans.

Breakthroughs by Design

Activators selective for the AMPKβ2-containing heterotrimers in liver and skeletal muscle will promote glucose uptake and fatty acid oxidation to improve glucose and lipid homeostasis, while reducing de novo lipogenesis and fibrosis.

Further Reading

Garcia, D. et al., Genetic liver-specific AMPK activation protects against diet-induced obesity and NAFLD (2019). Cell Reports 26, 192-208

Steinberg, G.R. et al., AMP-activated protein kinase: the current landscape for drug development (2019). Nature Reviews Drug Discovery 18, 527‐551

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