Autophagy Activator Drug Discovery Platform

VITA-FAST

Aging

Ageing is associated with the decline in the capacity of the autophagy pathway to degrade dysfunctional and damaging cellular components, such as protein aggregates and mitochondria. Dysfunctional autophagy, in turn, undermines other cellular functions including DNA repair, metabolism and survival. Therefore, activation of autophagy is considered a promising therapeutic approach to combat ageing and age-related diseases. A large number of screens has been performed and published to date, these have identified a wide range of small molecules that stimulate initiation of autophagy. Prof. Korolchuck lab proposes to initiate a drug discovery program with the aim of identifying novel bioactive autophagy inducers.

Owned by

0xf7990…96555

Contract:

0x6034e…33d36

Description

Team

Owner

Owner

Owner

Owner

Owner

Organisation

Newcastle University

Experiment Cost

$285,000.00

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

Price of VITA-FAST

$0.520

Project Progress

All updates

All categories

Timeline

Activity

Time	Type	$VITA-FAST	USD	ETH	From

Autophagy Activator Drug Discovery Platform

VITA-FAST

Aging

Owned by

0xf7990…96555

Contract:

0x6034e…33d36

Description

Team

Owner

Owner

Owner

Owner

Owner

Organisation

Newcastle University

Experiment Cost

$285,000.00

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

Price of VITA-FAST

$0.520

Project Progress

All updates

All categories

Timeline

Activity

Time	Type	$VITA-FAST	USD	ETH	From

Rationale

The project has conducted extensive in vitro experimental work, including high-throughput screening of thousands of compounds, three rounds of NCE synthesis and testing, target discovery experiments, and multiple orthogonal assay validations (cell survival, p62 clearance, LC3 traffic-light imaging) in Npc1-/- and Atg5-/- mouse embryonic fibroblasts. This clearly advances the project beyond TRL 1. However, no experiments have been conducted in disease-relevant in vivo models (Npc1-mutant mice/cats are planned but not yet conducted), and the C. elegans studies are ongoing/cancelled rather than completed with efficacy data. The primary experimental evidence comes from simplified 2D cell-based systems (immortalized MEFs), not from advanced disease-modeling systems such as patient-derived organoids or animal disease models demonstrating therapeutic efficacy, keeping the project at TRL 2.

Assessment

Low Confidence

RecommendationSUPPLEMENT

Total Score3.50

Overall Assessment

VITA-FAST scores 3.50 out of 5.00, reflecting a solid TRL 2 project with notable strengths and expected gaps for its maturity stage. The project's strongest dimension is therapeutic relevance (4/5, weighted 1.80), driven by robust target identification, validated assay biology, mechanism specificity demonstrated through elegant dual-cell-line controls, and strong publication support for the autophagy-NAD axis. The identification of two novel targets in H1 2025 and the 10-100x potency improvement in third-round NCEs represent meaningful scientific progress that reinforces the biological hypothesis.

Therapeutic optionality (4/5) is also strong, with the platform showing clear potential across NPC, broader lysosomal storage disorders, neurodegeneration, and longevity — though these remain conceptual extensions rather than experimentally validated alternative indications.

The middle-tier scores (3/5) for intellectual property, utility of candidates, and prospects for safety are appropriate for a TRL 2 project. IP is progressing with one patent filed and a legal entity established, but the critical composition-of-matter patents for novel NCEs remain pending. Drug candidates are emerging with encouraging potency trends, but lack formal quantitative characterization (EC50/IC50) and any in vivo validation. Safety data is limited to cellular viability observations, which is expected at this stage but leaves significant unknowns.

Key risks to monitor: (1) the second target (Autophagy2 family member) remains unconfirmed; (2) Round 2 NCE modifications failed to improve binding, suggesting SAR challenges; (3) no in vivo data of any kind exists yet; (4) the transition from computational optimization to validated lead compounds is a critical upcoming inflection point. The dual-track strategy (novel NCEs + repurposed compounds with Phase 1 data) is a strategic strength that partially mitigates development risk. Overall, the project demonstrates strong scientific foundations and is well-positioned for its TRL 2 stage, with clear next steps defined for advancement.

Weighted Score

Therapeutic Relevance

Early experimental results strongly support the hypothesis. Two novel autophagy-inducing targets (Autophagy1 confirmed, Autophagy2 family hypothesized) were identified in H1 2025, distinct from mTOR inhibition. Three rounds of NCE testing produced lead compounds with 10-100x higher potency than earlier series. The autophagy-NAD axis mechanism is validated across yeast, fly, mouse, and human models with strong publication support (Developmental Cell 2022, Cell Death & Disease 2024). The dual-cell-line assay (Npc1-/- vs Atg5-/-) demonstrates mechanism specificity — compounds rescue autophagy-competent cells but not autophagy-deficient cells, reinforcing biological relevance. Commercially available compounds binding the newly identified targets were independently validated as potent autophagy inducers, providing orthogonal confirmation. Score is 4 rather than 5 because formal EC50/IC50 values are not yet reported, the second target (Autophagy2 family member) is not yet confirmed (siRNA knockouts pending), and quantitative dose-response characterization is still ongoing.

Therapeutic Optionality

Emerging findings clearly suggest multiple alternative applications beyond the primary NPC indication. The two newly identified targets are described as 'previously proposed longevity targets,' opening pathways into aging/longevity therapeutics (global market projected $24.5B by 2032). The platform has demonstrated applicability to broader lysosomal storage disorders (~$9-11B market), neurodegeneration (Alzheimer's 50M+ patients, Parkinson's 10M+ patients), and potentially metabolic diseases. A parallel drug repurposing pathway has been identified with two lead repurposing molecules (with prior Phase 1 data) showing high potency in autophagy assays, creating a dual development track (NCEs + repurposing). The autophagy activation platform is described as having broad applicability including combination approaches with NAD+ precursors. Score is 4 rather than 5 because these alternative applications remain conceptual — no experimental validation in non-NPC disease models has been reported yet.

Intellectual Property

Early results are beginning to strengthen IP filings, and formalization has started. A patent application was filed on December 2, 2025 for repurposed compounds ('METHODS FOR ENHANCING AUTOPHAGY USING REPURPOSED PHARMACEUTICAL COMPOUNDS'), demonstrating that results are being translated into IP. VitaFast LLC (Delaware) has been formed to hold and manage project IP. The IP-NFT is registered on the Molecule protocol. Composition-of-matter patents for novel NCEs are planned for H2 2025/Q4 2025 but not yet filed. The screened compounds show high chemical variability and no similarity to pre-existing autophagy inducers, suggesting strong novelty for future filings. FTO position is described as favorable — novel mechanism distinct from mTOR inhibitors and existing NPC therapies. However, the score is 3 because: (1) only one patent has been filed (methods/repurposing, not composition-of-matter for the novel NCEs which are the core value); (2) novel compound IP filings are still planned/pending; (3) Newcastle University IP framework adds complexity; and (4) no patents have been granted yet.

Utility Of Candidates

Potential drug candidates are clearly emerging but viability for therapeutic effects is still being established. Three lead compounds have been identified from three rounds of NCE synthesis with 10-100x higher potency than previous series — a meaningful SAR progression. Additionally, two lead repurposing molecules with prior Phase 1 clinical history show high potency in autophagy assays, providing a faster-to-clinic backup pathway. Computational optimization against the two identified targets is now underway (VFDP-15), which should further improve candidates. However, the score is 3 because: (1) formal EC50/IC50 values have not been reported for any candidate; (2) no in vivo efficacy data exists yet; (3) Round 2 NCE structural modifications did not improve target binding over Round 1, indicating SAR challenges; (4) lead optimization is still in the computational/in silico phase; and (5) drug-like properties (ADMET, PK) have not been characterized for any candidate. The candidates are promising but their viability in achieving therapeutic effects in living systems remains undemonstrated.

Prospects For Safety

Early safety signals are cautiously positive but very limited in scope. No acute cytotoxicity was observed at therapeutic concentrations in cellular assays — a necessary but minimal safety indicator. The mechanism specificity (rescue in Npc1-/- but not Atg5-/- cells) suggests on-target activity rather than non-specific effects, which is a positive safety signal. The novel mechanism (distinct from mTOR inhibition) avoids the known immunosuppressive side effects of rapamycin/rapalogs. For the repurposing pathway, the two lead molecules have prior Phase 1 clinical safety data, significantly de-risking that track. Worm healthspan and longevity studies are described as ongoing. However, the score is 3 because: (1) no formal in vivo toxicology has been conducted; (2) no ADMET/DMPK profiling has been done; (3) GLP toxicology is entirely future/planned; (4) IND-enabling murine safety studies are not planned until 2026; and (5) the safety profile of the novel NCEs is essentially unknown beyond basic cellular viability. The risks appear manageable at this stage but are largely uncharacterized.