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Optimizing brain penetrance of caspase-6 inhibitors to treat neurodegenerative diseases

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AG078036-01A1
Agency Tracking Number: R41AG078036
Amount: $180,375.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: R
Solicitation Number: PAS19-317
Solicitation Year: 2019
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-30
Award End Date (Contract End Date): 2025-02-28
Small Business Information
San Diego, CA 92130-4850
United States
DUNS: 118072260
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 (858) 232-3642
Business Contact
Phone: (858) 531-8844
Research Institution
SAN FRANCISCO, CA 94143-2510
United States

 Nonprofit College or University

The cysteine protease caspase-6 (Casp6) has been associated with neurodegenerative diseases
for over fifteen years. In Alzheimer’s disease (AD), Casp6 is colocalized with amyloid plaques and
tau tangles in human brain, and both human and animal model data indicate that activated Casp6
contributes to neuronal inflammation, neurodegeneration, and cleavage of proteins to toxic forms.
Humans and mice lacking Casp6 are healthy and resistant to inflammation; furthermore, Casp6
knockout in 5xFAD mice bearing familial AD mutations in presenilin1 and amyloid beta precursor
protein (APP) show reduced levels in neuronal degeneration and inflammation. Thus, selective
inhibition of Casp6 could be safe and effective in treatment of AD. To this end, we propose to
design, synthesize and profile potent and highly selective inhibitors of the activated form of Casp6
(aCasp6) based on our initial SAR established for SU110 and SU134. These novel compounds
gain selectivity by binding covalently to a unique cysteine residue not found in other members of
the caspase family. While both SU110 and SU134 have promising drug-like properties, including
low nanomolar inhibition of aCasp6 in biochemical and cell-based assays, low toxicity, few off-
targets in proteome-wide studies, serum exposures 100-fold higher than cellular IC50, 50-77% oral
bioavailability, and up to 23% brain/plasma exposure, we will further explore the SAR to identify
compounds with improved PK and brain penetration properties (Aim 1). We will conduct standard
mouse PK experiments to determine oral bioavailability and to define structure–brain exposure
relationships. For Aim 2, we have developed a click-based probe of aCasp6 binding that
demonstrates sufficient potency and selectivity to use as an ex vivo activity-based probe of
aCasp6. We will use this probe, in conjunction with aCasp6 protein half-life determination and
measurement of the aCasp6 substrate tau, to determine the lifetime of target inhibition by
optimized aCasp6 inhibitors in cells; these data will be used in Phase II of the project to assess
target engagement in animals. From these SAR, PK and tissue distribution studies, we will identify
the most appropriate compounds to conduct PD assays and disease models to be run during
Phase II of the project. In the subsequent Phase II application, we will develop biomarker assays
and evaluate changes in these biomarkers after treatment with optimized lead compound in the
5xFAD model and additional animal models of AD. The conclusion of Phase II studies will be
refinement of the Target Candidate Profile and will anticipate the selection of a development
candidate for IND-enabling studies.

* Information listed above is at the time of submission. *

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