text stringlengths 1 5.46k |
|---|
Schedule 1.165 Research Plans See attached. |
SCHEDULE 1 RESEARCH PLANS |
Overview This research collaboration is focused on the discovery of monofunctional degrader compounds (molecular glues). Activities would involve Plexium synthesizing encoded and non-encoded libraries and executing screens using the Plexium platform to identify hits that would then progress through hit expansion/hit-to... |
SCHEDULE 1.1 RESEARCH PLAN FOR SOLUBLE OTUB1 DEGRADERS |
Objective Identify small molecules that degrade OTUB1 protein through direct binding to an E3 ligase (molecular glue mechanism) in human iPSC-derived neurons. OTUB1 degrader approach is expected to increase ubiquitination of soluble and oligomeric tau, facilitating its proteasomal clearance with potential to exert dise... |
Approach Utilize Plexium's DELPhe platform to generate putative E3 binder molecules, screen such molecules in ultra high throughput screens (UHTS) utilizing SH-SY5Y cells. The activity of hit compounds will be confirmed in iPSC-derived neurons for effects on tau aggregation. The goal is to discover small molecule E3 li... |
Cell lines/Model Systems The initial screening activities will be conducted in SH-SY5Y cells. The initial assay development will be to establish SH-SY5Y cell line performance in the DELPhe screening platform and validate the assay in pico/nano-well. The primary assay readout will be immunocytochemistry utilizing establ... |
Initial Library Generation The initial library will be cereblon-based with a bias towards compliant properties and will be synthesized in an iterative process. Regarding the total size of the initial library, the goal will be to generate an initial cereblon library of approximately 10,000 compounds to scan across chemi... |
Generation of Additional Libraries AbbVie will provide input and the parties shall agree upon the set of E3 ligases selected for generation of binders; the set of E3 ligases will have to be restricted towards those that have known binders and are expressed in neurons / neuronal cell lines. The overall goal is to select... |
DELPhe Screening Activities for Hit Identification Hit generation: Execution of DELPhe screens(s) to identify compounds that significantly reduce OTUB1 levels in SH-SY5Y cells (at least 50% degradation at ~ 1-10 µM concentration in 16 h to 24 hours). Hit confirmation and prioritization activities are outlined below: • ... |
Preliminary Hit Criteria (PHC): • Hit degradation potency: DC50 ≤ 10 µM confirmed for compounds in powder format with >85% purity. • Lack of cytotoxicity (CC50 at degradation EC90). |
Hit Expansion / Hit-to-Lead Additional libraries will be generated to support hit expansion of various hit series either in bead-based or parallel synthesis format. Iterative optimization will be performed to obtain with discernable SAR with ~ improved potency over initial hit compound in target degradation, or until i... |
Qualified Hit Criteria • Chemistry: Validated hit(s) should be on-compliancy (Ro5 parent scaffold, free from chemically reactive groups/structural alerts/known toxicophores) 5 ≤ MW ≤ 600. • A goal of delivering at least 2 chemotypes with discernable SAR with ~ 1-5 µM potency range / selectivity in degradation of target... |
AbbVie Support • Provide technical support (including internal protocols) to facilitate the utilization of human iPSC-derived neurons and other applicable cell model systems (to be determined based on prior validation datasets) (e.g., prioritizing compounds / chemotypes that are active in tau clearance assays in iPSCs)... |
OTUB1 Research Plan Data Package o Plexium will provide: o Summary and detailed datasets demonstrating achievement of Qualified Hit Criteria including all chemical and biological results associated with such hit series. o Plexium will also provide chemical and biological datasets of any hit series that satisfied Prelim... |
OTUB1 Research Plan Budget o Total budget amount is $5,900,000 o Execution of the research is expected to take approximately 6 to 7 calendar quarters o This Research Plan includes the cost for generation of the cereblon-biased library o This Research Plan includes the cost for structural enablement of up to 3 E3 ligase... |
SCHEDULE 1.2 RESEARCH PLAN FOR SOLUBLE TAU DEGRADERS |
Objective Identify small molecules that degrade soluble tau protein through direct binding to an E3 ligase (molecular glue mechanism) in human iPSC-derived neuronal cells. |
Approach Utilize Plexium's DELPhe platform to generate putative E3 binder molecules, screen such molecules in ultra-high throughput manner (sUHTS) utilizing iPSC-derived neurons. The overall goal is to discover small molecule E3 ligase binders with properties that meet or exceed Qualified Hit Criteria (QHC) that demons... |
Cell lines/Model Systems The priority cell type for screening is cortical neurons derived from human iPSCs (iPSC i3N line with inducible expression of NGN2 triple mutant) for rapid transdifferentiation of stem cells into neurons with an engineered tau locus. Protocols and conditions to be provided by AbbVie. |
Assay Development & Validation As noted above, assay development in the DELPhe screening platform will focus on human iPSC derived cells (i3Nci-N28 cells). Protocols and conditions will be provided by AbbVie, to enable assay validation at Plexium. The initial goal will be to establish and validate this assay in a nano-... |
Initial Library Generation The initial library will be cereblon-based with a bias towards compliant properties and will be synthesized in an iterative process. Regarding the total size of the initial library, the goal will be to generate an initial cereblon library of approximately 10,000 compounds to scan across chemi... |
Generation of Additional Libraries AbbVie will provide input and the parties shall agree upon the set of E3 ligases selected for generation of binders; the set of E3 ligases will have to be restricted towards those that have known binders and are expressed in CNS and microglia. The overall goal is to select a set of E3... |
DELPhe Screening Activities Hit generation: Execution of DELPhe screen(s) to identify compounds that significantly reduce soluble tau in cells (at least 50% degradation at ~ 1-10 µM concentration in 24 h) Hit confirmation and prioritization activities are outlined below: • Structure of hit compounds identified • Hit co... |
Preliminary Hit Criteria (PHC): • Hit degradation potency: DC50 ≤ 10 µM confirmed for compounds in powder format with >85% purity. • Lack of cytotoxicity (CC50 at degradation EC90). |
Library expansion / Hit-to-Lead Additional libraries will be generated to support hit expansion either in bead-based or parallel synthesis format. Iterative optimization will be performed to obtain at least 20 related molecules with discernable SAR with ~ improved potency over initial hit compound in target degradation... |
Qualified Hit Criteria o Chemistry: Validated hit(s) should be on-compliant: Ro5 parent scaffold, free from chemically reactive groups/structural alerts/known toxicophores) 5 ≤ MW ≤ 600. o Goal of delivering at least 2 chemotypes with discernible SAR with at least 1-5 µM potency range and selectivity in degradation of ... |
AbbVie Support • Provide technical support (including internal protocols) to facilitate the utilization of iPSC derived cortical neurons. • siRNAs and RNAi protocols as needed, to the degree reagents are not available from vendors. • Control/comparator compounds, if available. • Suggestions of E3 binders to be incorpor... |
Tau-soluble Research Plan Data Package o Plexium will provide: o Summary and detailed datasets demonstrating achievement of Qualified Hit Criteria including all chemical and biological results associated with such hit series. o Plexium will also provide chemical and biological datasets of any hit series that satisfied ... |
Soluble Tau Research Plan Budget o Total budget amount is $5,600,000 o Execution of the research is expected to take approximately 6 to 7 calendar quarters o The cost for generating the first library based off the first structure enabled E3 ligase binder is in this Research Plan budget (see next page) |
SCHEDULE 1.3 RESEARCH PLAN FOR SOLUBLE ALPHA-SYNUCLEIN DEGRADERS |
Objective Identify small molecules that degrade soluble alpha Synuclein (α-Syn) protein through direct binding to a known E3 ligase (molecular glue mechanism) in human iPSC-derived neuronal cells. |
Approach Utilize Plexium's DELPhe platform to generate putative E3 binder molecules, screen such molecules in ultra-high throughput screens (sUHTS) utilizing iPSC-derived neurons The overall goal is to discover small molecule E3 ligase binders with properties that meet or exceed Qualified Hit Criteria (QHC) that demons... |
Cell lines/Model Systems Assay development in the DELPhe screening platform will focus on the priority neuronal cells: human iPSCs (iPSC i3N line with inducible expression of NGN2). Protocols and conditions will be provided by AbbVie, to enable assay validation at Plexium. |
Assay Development & Validation As noted above, assay development in the DELPhe screening platform will focus on human iPSC derived cells (i3Nci-N28 cells). Protocols and conditions will be provided by AbbVie, to enable assay validation at Plexium. Validation datasets will include reliable quantification and reproducibi... |
Initial Library Generation The initial library will be cereblon-based with a bias towards compliant properties and will be synthesized in an iterative process. Regarding the total size of the initial library, the goal will be to generate an initial cereblon library of approximately 10,000 compounds to scan across chemi... |
Generation of Additional Libraries AbbVie will provide input and the parties shall agree upon the set of E3 ligases selected for generation of binders; the set of E3 ligases will have to be restricted towards those that have known binders and are expressed in neurons. The overall goal is to select a set of E3 ligases, ... |
DELPhe Screening Activities Hit generation: Execution of DELPhe screen(s) to identify compounds that significantly reduce soluble alpha synuclein in cells (>50% degradation at ~ 1-10 µM concentration in 24 h). Hit confirmation and prioritization activities are outlined below: • Structure of hit compound identified • Hi... |
Preliminary Hit Criteria (PHC): • Hit degradation potency: DC50 ≤ 10 µM confirmed for compounds in powder format with >85% purity. • Lack of cytotoxicity (CC50 at degradation EC90). |
Library Expansion / Hit to Lead Additional libraries will be generated to support hit expansion either in bead-based or parallel synthesis format. Iterative optimization will be performed to obtain at least 20 related molecules with discernable SAR with ~ improved potency over initial hit compound in target degradation... |
Qualified Hit Criteria • Chemistry: Validated hit(s) should be on-compliant: Ro5 parent scaffold, free from chemically reactive groups/structural alerts/known toxicophores) 5 ≤ MW ≤ 600. • Goal of delivering at least 2 chemotypes with discernible SAR with at least 1-5 µM potency range and selectivity in degradation of ... |
AbbVie Support • Provide technical support (including internal protocols) to facilitate the utilization of iPSC derived neurons. • siRNAs and RNAi protocols as needed, to the degree reagents are not available from vendors. • Control/comparator compounds, if available. • Suggestions of E3 binders to be incorporated base... |
Syn Soluble Research Plan Data Package o Plexium will provide: o Summary and detailed datasets demonstrating achievement of Qualified Hit Criteria including all chemical and biological results associated with such hit series. o Plexium will also provide chemical and biological datasets of any hit series that satisfied ... |
Soluble Alpha-Synuclein Research Plan Budget o Total budget amount is $5,600,000 o Execution of the research is expected to take approximately 6 to 7 calendar quarters o The cost for generating the second library based off the second structure enabled E3 ligase binder is in this Research Plan budget (see next page) o |
SCHEDULE 1.4 RESEARCH PLAN FOR TAU AGGREGATE DEGRADERS |
Objective Identify small molecules that induce clearance of tau protein in pathogenic inclusions in cell based assay through the Ubiquitin Proteasome System or by engaging other degradation pathways (e.g., autophagy, including chaperone mediated autophagy) |
Approach Utilize Plexium's DELPhe platform to generate property compliant, random diversity library based upon core scaffolds generated from known BBB penetrating compounds, including tau-binding PET ligands; screen such molecules in ultra high throughput screens (UHTS) using iPSC derived neurons pre-incubated with tau... |
Cell lines/Model Systems Priority cells to be used are human iPSC-derived cortical neurons generated from neuronal precursor cells by dual SMAD inhibition (AbbVie 30-iN/i4N) also referred to (tau 4R+ neurons). Neuronal progenitor cells, protocols and conditions will be provided by AbbVie. |
Assay Development & Validation As noted above, assay development in the DELPhe screening platform will focus on the priority cell line, i.e., human tau 4R+ neurons. Neuronal precursor cells, protocols and conditions as well as technical support will be provided by AbbVie, to enable assay validation at Plexium. The init... |
Initial Library Generation A random diversity library with a bias towards compliant properties will be generated The overall library size will be determined by analysis of multiple iterative square matrix, based on various considerations including type of chemistry, availability and cost of monomers, BBB penetration, e... |
DELPhe Screening Activities Hit generation: Execution of DELPhe screen(s) to identify compounds that clear or significantly reduce tau aggregates in cells (e.g., >50% reduction at ~ 1-10 µM concentration in 18 or 24 h) Hit confirmation and prioritization activities are outlined below: • Structure of selected hit compou... |
Preliminary Hit Criteria (PHC): • Hit degradation potency: DC50 ≤ 10 µM confirmed for compounds in powder format with >85% purity. • Lack of cytotoxicity (CC50 at degradation EC90). |
Library Expansion / Hit-to-Lead Additional libraries based on prioritized series will be generated to support hit expansion either in bead-based or parallel synthesis format. Iterative optimization will be performed to obtain at least 20 related molecules with discernable SAR with ~ improved potency over initial hit co... |
Qualified Hit Criteria • Chemistry: Validated hit(s) should be on-compliant: Ro5 parent scaffold, free from chemically reactive groups/structural alerts/known toxicophores) 5 ≤ MW ≤ 600. • Clearance Profile: Goal of delivering at least 2 chemotypes with discernible SAR with ~ potency range in clearance of tau aggregate... |
AbbVie Support • Provide technical support (including internal protocols) to facilitate the utilization of PHF pre-treated iPSC derived cortical neurons based on AbbVie established differentiation protocols and to support MOA experiments (knockout cell lines, organelle marker cell lines or reagents) • siRNAs and RNAi p... |
Tau Aggregate Degrader Research Plan Data Package o Plexium will provide: o Summary and detailed datasets demonstrating achievement of Qualified Hit Criteria including all chemical and biological results associated with such hit series. o Plexium will also provide chemical and biological datasets of any hit series that... |
Tau Aggregate Degrader Research Plan Budget o Total budget amount is $5,700,000 o Execution of the research is expected to take approximately 6 to 7 calendar quarters o This research plan includes the cost for generation of the 75K diversity library |
SCHEDULE 1.5 RESEARCH PLAN FOR ALPHA SYNUCLEIN AGGREGATE DEGRADERS |
Objective Identify small molecules that induce clearance of alpha Synuclein (α-syn) protein in pathogenic inclusions in cell based assays, through the Ubiquitin Proteasome System or by engaging other degradation pathways (e.g., autophagy including chaperone mediated autophagy,) |
Approach Utilize Plexium's DELPhe platform to generate a property compliant, random diversity library of compounds based upon core scaffolds generated from known BBB penetrating compounds, screen such molecules in ultra high throughput screens (sUHTS) utilizing iPSC derived dopaminergic neurons pre-incubated with α-syn... |
Cell lines/Model Systems Priority cells to be used are human iPSC derived dopaminergic neurons (neuronal precursor cells, protocols and conditions will be provided by AbbVie) |
Assay Development & Validation As noted above, assay development in the DELPhe screening platform will focus on the priority cell line, i.e., human iPSC derived dopaminergic neurons. Neuronal precursor cells, protocols and conditions as well as technical support will be provided by AbbVie, to enable assay validation at... |
Initial Library Generation A random diversity library with a bias towards compliant properties will be generated The overall library size will be determined by analysis of multiple iterative square matrix, based on various considerations including type of chemistry, availability and cost of monomers, BBB penetration, e... |
DELPhe Screening Activities Hit generation: Execution of DELPhe screen(s) to identify compounds that clear or significantly reduce α-syn aggregates in cells (e.g., >50% reduction at ~ 1-10 µM concentration in 18 or 24 h). Hit confirmation and prioritization activities are outlined below (select compounds from each clus... |
Preliminary Hit Criteria (PHC): • Hit degradation potency: DC50 ≤ 10 µM • Lack of cytotoxicity (CC50 at degradation EC90). |
Library Expansion / Hit-to-Lead Additional libraries based on prioritized series will be generated to support hit expansion either in bead-based or parallel synthesis format. Iterative optimization will be performed to obtain at least 20 related molecules with discernable SAR with ~ improved potency over initial hit co... |
Qualified Hit Criteria • Chemistry: Validated hit(s) should be on-compliant: Ro5 parent scaffold, free from chemically reactive groups/structural alerts/known toxicophores) 5 ≤ MW ≤ 600. • Clearance / degradation Profile: Goal of delivering at least 2 chemotypes with discernible SAR with ~ potency range in clearance of... |
AbbVie Support • Provide technical support (including internal protocols) to facilitate the utilization of PFF pre-treated iPSC-derived dopaminergic neurons and to perform MOA experiments (knockout cell lines, organelle marker cell lines or reagents) • siRNAs and RNAi protocols to the degree reagents are not available ... |
Syn Aggregate Research Plan Data Package o Plexium will provide: o Summary and detailed datasets demonstrating achievement of Qualified Hit Criteria including all chemical and biological results associated with such hit series. o Plexium will also provide chemical and biological datasets of any hit series that satisfie... |
Syn Aggregate Degrader Research Plan Budget o Total budget amount is $5,200,000 o Execution of the research is expected to take approximately 6 to 7 calendar quarters o The cost for generating the third library based off the third structure enabled E3 ligase binder is in this Research Plan o |
Schedule 3.2.3 Permitted Subcontractors |
Subcontractor Subcontractor Address General Scope of Work (subject to adjustment) |
Wuxi AppTec (Hong Kong) Limited WuXi AppTec (HongKong) Limited Unit C, 20/F., OfficePlus @ Mong Kok, No. 998 Canton Road, Kowloon, Hong Kong In vitro ADME and rodent in vivo PK on synthetic compounds |
Wuxi AppTec WuXi AppTec Building 1, 288 Fute Zhong Road Waigaoqiao Free Trade Zone Shanghai, China 200131 Synthesis of intermediates and monomers used in preparing libraries |
Cresset Biomolecular Discovery Limited New Cambridge House, Bassingbourn Road, SGS088, United Kingdom Molecular modeling studies and structure activity relationships using proprietary technology |
Schedule 7.7.1 Example Royalty Calculations |
If (a) annual Net Sales of Licensed Product No. 1 is $2.2 billion Dollars in a Calendar Year, (b) annual Net Sales of Licensed Product No. 2 is $1.800 million Dollars, and (c) Licensed Product No. 3 is $400 million Dollars, all in the same Calendar Year, the amount due to Plexium for such Calendar Year would be $176 mi... |
Schedule 10.2 Plexium Disclosures |
None. |
Schedule 10.2.1 Existing Patents |
See attached. |
TITLE COUNTRY STATUS APPLICATION NUMBER FILING DATE PUBLICATION NUMBER PUBLICATION DATE PATENT NUMBER GRANT DATE |
FLUIDIC DEVICE AND METHOD US Completed 63/046,500 06/30/2020 |
FLUIDIC DEVICE AND METHOD US Pending 17/364,710 06/30/2021 |
FLUIDIC DEVICE AND METHOD WO Pending PCT/US2021/039839 06/30/2021 |
TRANSFER DISPENSERS FOR ASSAY DEVICES WITH BEAD SIZE EXCLUSION US Pending 63/197,972 06/07/2021 |
ASSAY DEVICES FOR COMBINATORIAL LIBRARIES US Published 16/774,862 01/28/2020 US-2021-0229087-A1 07/29/2021 |
TRANSFER DISPENSERS FOR ASSAY DEVICES US Issued 16/774,871 01/28/2020 11,027,272 06/08/2021 |
CAPS FOR ASSAY DEVICES US Issued 16/774,875 01/28/2020 11,040,343 06/22/2021 |
CAPS FOR ASSAY DEVICES US Pending 17/353,693 06/21/2021 |
COMPOSITIONS AND METHODS FOR OLIGONUCLEOTIDE ENCODED LIBRARIES US Completed 62/562,905 09/25/2017 |
COMPOSITIONS AND METHODS FOR SCREENING COMPOUND LIBRARIES ON SINGLE CELLS US Completed 62/562,912 09/25/2017 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES US Abandoned 16/139,831 09/24/2018 US 2019-0210018 A1 07/11/2019 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES US Issued 16/534,886 08/07/2019 US 2019-0358629 A1 11/28/2019 10,828,643 11/10/2020 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES US Issued 16/870,809 05/08/2020 US 2020-0324287 A1 10/15/2020 10,981,170 04/20/2021 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES US Pending 17/200,538 03/12/2021 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES WO Expired PCT/US2018/052438 09/24/2018 WO 2019/060830 03/28/2019 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES CA Pending 3,076,747 09/24/2018 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES CN Pending 201880072082.7 09/24/2018 111971124 11/20/2020 |
OLIGONUCLEOTIDE ENCODED CHEMICAL LIBRARIES EP Published 18859564.9 09/24/2018 3687687 08/05/2020 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.