RESEARCH AND DEVELOPMENT

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ARV-393 is an investigational PROTAC designed to degrade B-cell lymphoma 6 protein (BCL6) which is a transcriptional repressor implicated in B cell lymphomas by facilitating B cell tolerance of rapid proliferation and somatic gene recombination via repressing cell cycle checkpoints, terminal differentiation, apoptosis, and the DNA damage response. PROTAC-mediated degradation would address the scaffolding function of BCL6. BCL6 has completed investigational new drug (IND)-enabling studies.

Hematopoietic progenitor kinase 1 (HPK1) is a suppressor of T cell activation, and targeting HPK1 can enhance anti-tumor immune responses PROTAC-mediated degradation has the potential to address the proposed scaffolding component of HPK1’s activity.

Kirsten rat sarcoma (KRAS) has historically been considered a “undruggable” target due to its lack of deep “pockets” and is associated with poor prognosis and resistance to standards of care in several tumor types. Arvinas is developing pan-KRAS mutant and mutant-specific KRAS degraders G12D.

Myelocytomatosis (Myc) proteins are implicated in up to 70% of all human cancers. Targeting Myc indirectly, such as by inhibiting transcription modulators, has not been successful, but PROTAC-mediated degradation has the potential to directly target and degrade Myc.

ARV-102 is an investigational PROTAC designed to degrade Leucine-rich repeat kinase 2 (LRRK2) which is a large multidomain scaffolding kinase. Human genetics, increased activity and expressions of LRRK2 is genetically involved in the pathogenesis of neurological diseases including Parkinson’s Disease and progressive supranuclear palsy. Arvinas is developing oral, blood-brain-barrier penetrant PROTAC degraders of LRRK2.

The pathologic aggregation of α-synuclein is a key driver in many synucleinopathies, including multiple system atrophy and Parkinson’s disease. Our PROTAC protein degraders specifically degrade oligomeric forms of α-synuclein, which forms disease-causing aggregates. More information is available here.

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene. PROTAC degradation has the potential to allow the selective targeting of mutant HTT protein without impacting wild-type HTT protein.

Tau is a key disease driver in many tauopathies, including Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau), Alzheimer’s disease and progressive supranuclear palsy (PSP). Our PROTACs target pathogenic tau without degrading healthy forms of tau. More information is available here.