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.

Nimbus Programs

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 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 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

HPK1
Key regulator of T cell, B cell and dendritic cell-mediated immune responses
Clinical

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.

Clinical Trial Information

Nimbus has initiated a Phase 1/2 clinical trial that is evaluating the safety/tolerability and preliminary anti-tumor activity of its HPK1 inhibitor in patients with solid tumors.

Expanded Access Statement

Expanded access, or compassionate use, is the use of an investigational medicine prior to regulatory approval and outside of a clinical trial. Nimbus does not currently have an expanded access program for any of our investigational products. We encourage patients to speak with their physician about options that may be right for them including ongoing clinical trials and approved medicines.

Further Reading

Hernandez, S. et al., The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function (2018). Cell Reports 25, 80-94

Liu, J. et al., Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance (2019). PLOS One 14, e0212670

Alzabin, S. et al., Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation (2009). Journal of Immunology 182, 6187-94

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

AMPK
Canonical regulator of major cellular energy balance for a broad range of metabolic disorders
Discovery

Target Selection

AMPK 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, kidney and other tissues has profound impact in metabolic disease models; small molecule activation of AMPK has long been recognized as a potential strategy to treat disorders with deregulated metabolism.

Approach

AMPK is a heterotrimer comprised of α, β and γ subunits; two isoforms of β exist. We are using structural biology combined with computational chemistry approaches to identify isoform-selective, small molecule activators of AMPK heterotrimers.

Breakthroughs by Design

Isoform-selective activators of AMPK will positively affect cellular energetics and metabolic homeostasis for a broad range of metabolic disorders.

Collaboration Partnership

In October 2022, Nimbus and Eli Lilly and Company (Lilly) entered into a research collaboration and exclusive, worldwide license agreement for the development and commercialization of novel targeted therapies that activate a specific isoform of AMPK for the treatment of metabolic diseases. Nimbus will be responsible for research activities, and Lilly will be responsible for development and commercialization activities worldwide. Financial consideration for Nimbus includes a series of payments, funding and milestones spread through research, development and commercialization. Learn more.

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

Partner Programs

ACC
Potent, liver-targeted allosteric inhibition of isoforms to target non-alcoholic steatohepatitis and other diseases

Acetyl-CoA carboxylase (ACC) is an enzyme that is involved in de novo lipogenesis (the synthesis of endogenous fatty acids) and the regulation of beta-oxidation (the process by which fatty acids are broken down at a cellular level). Nimbus developed ACC inhibitors, including NDI-010976, for the treatment of non-alcoholic steatohepatitis (NASH) and potentially hepatocellular carcinoma and other diseases. In May 2016, Gilead acquired Nimbus’ ACC inhibitor program, with an upfront payment of $400 million and potential for an additional $800 million in development-related milestones.

TYK2
Allosteric inhibition to address autoimmune disorders with compelling human genetics

TYK2 (tyrosine kinase 2) is an important signal-transducing kinase implicated in immune-mediated diseases. Nimbus discovered and developed highly selective, allosteric TYK2 inhibitors, including NDI-034858, which Nimbus evaluated in Phase 2 studies in moderate-to-severe psoriasis and psoriatic arthritis. Preclinical and clinical data demonstrated the molecule’s best-in-class potential in the new therapeutic class of TYK2 inhibitors. In February 2023, Takeda acquired Nimbus’ TYK2 program, with Nimbus receiving an upfront payment of $4 billion, with potential to receive up to $2 billion in commercial milestone payments.

Our Pipeline

 

  •  
  • DISCOVERY
  • PRECLINICAL
  • CLINICAL
HPK1
Clinical
AMPK*
Discovery
CTPS1
Discovery
Cbl-b
Discovery
WRN
Discovery

*In collaboration with

Publications and Presentations

Publications
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posters & abstracts

Discovery of NTX-801, a Cbl-b inhibitor with anti-tumor activity in syngeneic models

Presented at: AACR 2022

Authors: David Ciccone, Fred Csibi, Christopher Plescia, David L. Laughton, Beth Browning, Suzanne L. Jacques, Angela V. Toms, Samantha Garside, Simon D’Archivio, Eric Feyfant, Fiona McRobb, Salma Rafi, Yan Zhang, Katarzyna Kopycka, Stuart Thomson, Allan M. Jordan, Tom Baker, Puter Tummino, Scott Edmondson, Christine Loh, Xiaohua Zhu, and Silvana Leit.

A Highly Selective and Potent HPK1 Inhibitor Induces Robust Tumor Growth Inhibition as a Single Agent and in Combination with anti-PD1 in Multiple Syngeneic Tumor Models

Presented at: AACR 2021

Authors: David Ciccone, Vad Lazari, Ian Linney, Michael Briggs, Samantha Carreiro, Ben Whittaker, Stuart Ward, Grant Wishart, Eric Feyfant, Jeremy Greenwood, Abba Leffler, Alexandre Cote, Steven Albanese, Ian Waddell, Chris Hill2, Christine Loh, Peter Tummino, Joshua McElwee, Alan Collis, and Neelu Kaila

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