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.

Our Pipeline

 

  • TARGET
  • DISCOVERY
  • LEAD OPTIMIZATION
  • PRECLINICAL
  • CLINICAL
HPK1 (Oncology)
THERAPY AREA: Oncology
TARGET: HPK1
Clinical
WRN (Oncology)
THERAPY AREA: Oncology
TARGET: WRN
Lead Optimization
SIK (Immunology)
THERAPY AREA: Immunology
TARGET: SIK
Lead Optimization
cGAS (Immunology)
THERAPY AREA: Immunology
TARGET: cGAS
Discovery
AMPK* (Metabolic)
THERAPY AREA: Metabolic
TARGET: AMPK*
Discovery

*In collaboration with

In addition to the above programs, Nimbus has an evergreen list of undisclosed targets in immunology, oncology, and metabolic disorders.

Nimbus Programs

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

Target Selection

HPK1 (hematopoietic progenitor kinase 1) is a MAP4K family kinase that negatively regulates T cells, B cells, and dendritic cells. 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 developed a reversible, ATP-competitive HPK1 inhibitor (NDI-101150) using a comprehensive approach combining structural biology, physics-based computational chemistry, and medicinal chemistry. NDI-101150 is highly potent and highly selective over other MAPK4 and immune receptor kinases, with features distinct from the anti-PD1 checkpoint inhibitor.

Breakthroughs by Design

NDI-101150 enhances activation of not only T cells, but also B cells and dendritic cells, to mount a robust anti-tumor response, even under immunosuppressive conditions. NDI-101150 shows excellent target engagement in vivo, and mediates significant tumor growth inhibition in syngeneic murine tumor models both as a single agent and in combination with a checkpoint inhibitor.

Clinical Trial Information

Nimbus has initiated a Phase 1/2 clinical trial (NCT05128487) 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

NDI-101150 is a Potent and Highly Selective Hematopoietic Progenitor Kinase 1 (HPK1) Inhibitor that Promotes a Robust and Broad Anti-Tumor Immune Response

Presented at: SITC 2023
Authors: David Cicone, Fu-Shan Kuo, Scott Boiko, Scott Daigle, Samantha Carreiro, Neela Kaila, Gene Yau, Esha A. Gangolli, Denise Lavasseur, Bhaskar Srivastava, Frank G. Basile, and Christine Loh

Preliminary Monotherapy and Pharmacokinetic Results from an Ongoing Phase 1a Dose Escalation Study of NDI-101150, a Highly Selective Oral Hematopoietic Progenitor Kinase 1 (HPK1) Inhibitor.

Presented at: SITC 2023
Authors: David Sommerhalder, Marcus Noel, Scott Boiko, Scott Daigle, Xinyan Zhang, Patricia Fraser, Amanda Hoerres, Nawaid Rana, Esha A. Gangolli, Frank G. Basile, Bhaskar Srivastava, Sunil Sharma, Rama Balaraman, and Martin Gutierrez

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

WRN
Selectively targeting a synthetic lethal dependency of microsatellite instable tumors
Lead Optimization

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 have developed potent, selective WRN inhibitors that are active in vivo and result in tumor regressions of MSI-high tumors in xenograft mice.

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

SIK
Modulating pathways to restore homeostasis and prevent disease progression
Lead Optimization

Target Selection

The family of salt-inducible kinases are involved in regulation of transcriptional programs that activate pathological processes and inhibit repair mechanisms. SIK inhibitors are thus expected to correct this imbalance by interrupting pathological pathways and permitting repair.

Approach

The biological roles of the SIKs are complex. We are designing SIK inhibitors with precise selectivity profiles and characterizing their pharmacology to target specific disease states.

Breakthroughs by Design

Inhibitors of SIK family members offer potential differentiation from current treatments by attenuating tissue destruction and promoting the resolution of pathology.

Further Reading

Darling, N.J. and Cohen, P. Nuts and bolts of the salt-inducible kinases (SIKs) (2021) Biochemical Journal 478, 1377–1397 

Sakamoto, K. et al.  The Salt-Inducible Kinases: Emerging Metabolic Regulators (2018) Trends in Endocrinology and Metabolism 29, 827-840 

Sundberg, T.B. et al. Development of Chemical Probes for investigation of Salt-Inducible Kinase Function in Vivo (2016) ACS Chem. Biol. 11, 2105-2111

cGAS
Targeting the pathological activation in autoimmune and other potential indications
Discovery

Target Selection

cGAS (cyclic GMP-AMP synthase) is a component of the innate immune system that senses cytosolic dsDNA and initiates an inflammatory cascade. cGAS activates the protein STING (stimulator of interferon genes), which propagates a pro-inflammatory response culminating in the activation of the type I interferon and NF-kB pathways. The cGAS-STING pathway is a key driver of inflammation in autoimmune and other diseases.

Approach

We are designing potent and selective inhibitors of cGAS that exploit the natural dynamics of the binding pocket through structure enablement and computational chemistry.

Breakthroughs by Design

Selective and potent inhibitors of cGAS have the potential to suppress innate immune activation for the treatment of immune-mediated inflammatory disorders. 

Further Reading

Skopelja-Gardner et al., Role of the cGAS-STING pathway in systemic and organ-specific diseases (2022). Nat Rev Nephrol., 18(9): 558-572.

Decout et al., The cGAS-STING pathway as a therapeutic target in inflammatory diseases (2021). Nat Rev Immunol. Sep;21(9):548-569.  

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

Acquired Programs

These programs were developed by Nimbus and then acquired by leading biopharmaceutical companies.
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.

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

A Highly Selective and Potent HPK1 Inhibitor Enhances Immune Cell Activation and Induces Robust Tumor Growth Inhibition in a Syngeneic Tumor Model

Presented at: SITC 2020

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 Hill, Christine Loh, Peter Tummino, Joshua McElwee, Alan Collis, and Neelu Kaila View recorded webinar >

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