VFDP-11: Approval of budget to seek advice and order new chemical compounds

Context

During H1 2024 the VITA-FAST project screened 86 derivatives of 21 compound series identified during primary screening. From these 86 compounds three lead series (VF01, VF02, VF05) have been identified. The next phase of experiments is to, in tandem, optimise the Structure Activity Relationship (SAR) of these compounds to make them more potent & find the Targets of the compounds in these series. This is the “Hit-to-Lead” phase of drug development.

These compounds will be tested in the same chemical assays at the University of Newcastle that have been used to select the lead series, these are: ATG/NPC Cell survival - primary assay for establishing induction of autophagy P62 clearance - secondary assay for establishing p62 clearance indicating autophagy rescue LC3 clearance - orthogonal assay indicating successful autophagosome-lysosome fusion and autophagy completion

This purchase will take approximately 2 months for new compounds to arrive with data arriving in Q4. These experiments form part of the H2’24 experimental plan that will be communicated with the community during July however this purchase is the longest lead time component as it involves new chemical synthesis by a supplier and hence budget approval is sought in advance.

This proposal seeks budget approval for up to $45,000 to seek additional medicinal chemistry input on the compounds selected and to synthesise 60 custom compounds with which to understand SAR.

Proposal Details:

(1) Firstly this proposal seeks to allocate up to 10 hours work (max cost $2,030) with Camp Consulting to review the experimental data and provide strategic feedback on the combined SAR and Target Discovery experiments in the next phase. Camp Consulting previously consulted for this project in Q4’23 (VFDP-2) and provided valuable insight into the developmental viability of each of the 21 compound series. We seek approval for up to 10 hours work with Camp Consulting, any unspent hours will be returned to the treasury.

(2) Secondly to move forwards from the three lead series and explore SAR the project team have designed 20 variations to each of the three lead series (60 compounds total) that explore the nearby chemical space. This is designed to allow the medicinal chemists to understand which aspects of the chemical structures are driving the performance and which are holding it back. Importantly these variations are New Chemical Entity and with this step VITA-FAST will be working with previously undescribed chemical matter that is fertile ground for future IP. In addition to the 60 NCE variations there are 11 cheaply available commercial derivatives of series VF05 that allow for cheap expansion of the experiment scope.

Multiple quotes for compound synthesis were obtained and the most attractive cost and timeline was selected. We seek approval for up to $41,000 in order to purchase these compounds from SYNmed Chem + $1,100 to purchase the commercial derivatives of VF05.

Funding Source

The funds will be appropriated from the existing VITA-FAST treasury. No external fundraising is required.

Contracts

All work will be conducted under standard supplier contracts whereby VITA-FAST retains all ownership of resulting matter, data & IP.

Recommendation

(1) The services of Camp Consulting were invaluable to the project in Q4’23 to refine compound choices to pursue. Now is a key moment in the project to check in on the data about those compounds and review the manner in which the compound derivatives will be explored. It is recommended that this expert advice is sought.

(2) The ordering of new chemical matter with which to optimise SAR and explore targets is the next exciting phase of this project for the team to further understand these brand new mechanisms. It is recommended that these compounds are purchased to allow the project to continue.