US20240300921A1 — Indole-substituted Quinolines + Plk1 Inhibitor SAR
A focused 40-compound library of 2-aminoquinoline analogs evaluated against LS174T colon cancer cells, with a headline Plk1 combination synergy claim. This page presents the complete 95-record SAR readout, multi-dimensional descriptor profile, and 211 activity-cliff comparisons — auto-extracted from the patent by Eureka LS.
Indole-substituted quinolines (ISQs) sit at the intersection of two long-standing oncology chemotypes — the quinoline scaffold familiar from kinase inhibitors and the indole pharmacophore central to a generation of anti-proliferative agents. Patent US20240300921A1 formalises a focused library of 40 such compounds and pairs them with a Plk1 inhibitor combination claim, framing the series as a treatment for c-MYC-driven cancers.
This page presents the full SAR readout of the patent in a single, navigable view: every compound code, every dose-response point, the multi-dimensional descriptor profile, and the most informative activity-cliff comparisons — all extracted automatically by Eureka LS. The aim is to make the patent's chemistry searchable rather than locked inside a 60-page PDF.
What the patent claims, in one paragraph.
Indole-substituted quinolines presented as anti-proliferative agents for c-MYC-driven cancers, optionally combined with a polo-like kinase 1 (Plk1) inhibitor.
The disclosure covers a series of 2-aminoquinolines bearing an indole, benzofuran, benzothiazole, or thiazole substituent at the 3-position, and a basic amine — most commonly N(Me)2, NHMe, piperidine, piperazine, pyrrolidine, or morpholine — at the 7-position. The shared scaffold is captured by the SMARTS pattern Nc1nc(cc(cc2)[R2])c2cc1[R1], which matches every one of the 40 disclosed analogs.
Activity is measured as cell-proliferation inhibition in LS174T colon-cancer cells (a c-MYC-driven CRC model), assayed via culture-medium addition over a 5-day endpoint. Doses span four orders of magnitude — 62 nM, 125 nM, 250 nM, 500 nM, 1 µM and 3 µM — and several compounds appear at multiple doses, giving partial dose-response curves rather than single-point screens.
The patent's distinguishing therapeutic claim is the combination with a Plk1 inhibitor. Co-dosing the lead compound ISQ-1 with BI2536 (a clinical Plk1 inhibitor) yields a Bliss synergy score of 10.56, comfortably above the +5 threshold that conventionally separates synergy from additivity.
across 40 unique compounds
LMK-5-67 @ 3 µM
ISQ-1 + BI2536
5-level dose-response
oral-bioavailable space
p-OMe-benzothiazoles
Compound nomenclature
The patent uses three internal code prefixes that group analogs by synthetic series:
- ISQ-n (ISQ-1 through ISQ-10) — the named lead series, primarily 1-methylindole-substituted quinolines with varied 7-position amines.
- VMS-n-m (e.g. VMS-7-7, VMS-8-67) — a synthetic exploration series including benzofuran, benzothiazole, and dichlorophenyl R1 variants.
- LMK-n-m (e.g. LMK-5-67, LMK-6-89) — the largest series, covering thiazole-aryl, fluorophenyl, and modified piperidine R2 variants.
Five things the SAR data tells us.
Distilled from the full 95-record dataset and the multi-dimensional descriptor profile.
Nc1nc(cc(cc2)[R2])c2cc1[R1]. SAR variation is concentrated at two positions: R1 (a heteroaryl on quinoline-3) and R2 (a basic amine on quinoline-7). This makes the patent unusually clean to triage — the chemistry space is small and well-defined."Out of 95 measurements, the most informative single number is not the best inhibition — it is the Bliss synergy of 10.56 between ISQ-1 and BI2536." — Eureka LS, automated SAR analysis of US20240300921A1
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95 activity records, 40 compounds, one cell line.
Below is a top-activity preview from the full extraction. The complete dataset — including every dose-response point, SMILES, dosing regimen, and source-page citation — is available in Eureka LS.
The patent reports cell-proliferation inhibition for 40 unique compounds, evaluated at up to six different concentrations each, yielding 95 individual activity measurements. Inhibition values range from 2% (LMK-6-99 at 62 nM) to 99.8% (LMK-5-67 at 3 µM). The distribution skews bimodal — 47 records report ≥80% inhibition, 36 report <50%, with relatively few in between — reflecting the dose-response nature of the underlying assay.
| Compound | Subject | Indicator | Dose | Inhibition | Activity |
|---|
Beyond raw activity — the descriptor profile of the series.
Eureka LS auto-computes physicochemical descriptors, druglikeness, ligand efficiency, mutagenicity, and scaffold/ring decomposition for every extracted compound.
The 40 ISQ analogs occupy a tight, well-behaved region of physicochemical space. Lipophilicity (CLogP) ranges from 3.31 to 6.03 — most compounds sit comfortably in the lead-like 3-5 window, with three outliers above 5 that warrant permeability checks. Topological polar surface area is uniformly below the 90 Ų oral-bioavailability threshold, confirming the series is well-suited to oral dosing.
Nc1nc(cc(cc2)[R2])c2cc1[R1] — shared by all 40 analogs.Compound-level descriptor profile
Below is the descriptor breakdown for the 12 most active compounds, the natural starting set for downstream lead optimisation.
| Compound | Inhibition | CLogP | TPSA | Druglikeness | Ames | R1, R2 substituents |
|---|
The single-bond changes that move the needle.
Activity cliffs — pairs of structurally similar compounds with sharply different activity — pinpoint exactly which substituents drive SAR. Eureka LS auto-generated 211 such pairs across the patent.
Of the 211 pairwise comparisons, 12 qualify as canonical activity cliffs (Tanimoto similarity > 0.85, Δ inhibition > 50%). Five of these are reproduced below — chosen because they isolate one specific design choice each.
What this dataset means for an ISQ-class program.
A short reading of the chemistry, the SAR, and the open questions the patent leaves on the table.
Read end to end, US20240300921A1 reads less like a tour of medicinal-chemistry possibility space and more like a focused defense of a single combination claim. The 2-aminoquinoline scaffold is fixed across all 40 analogs; the chemistry exploration is concentrated at two positions; and the most differentiated readout in the entire dataset is not a single-agent IC50 but the Bliss synergy between ISQ-1 and a Plk1 inhibitor.
For a program looking to build on this disclosure, three observations are worth flagging:
- Single-agent potency saturates quickly. Roughly half the library exceeds 90% inhibition at 3 µM, which means that 3 µM is a poorly discriminating screening dose. The interesting separation happens at 250–500 nM, where the ISQ-7/8/9/10 sub-series and ISQ-3 pull away from the rest. Future SAR triage should set screening doses at this lower range.
- The Plk1 combination is the IP. The strongest empirical signal in the patent is the synergy with BI2536. A program that develops the single-agent without the combination story risks duplicating an already-disclosed chemotype without claiming the differentiated mechanism.
- Two compounds carry mutagenicity flags that are easy to fix. LMK-5-62 and LMK-5-68 both contain a p-methoxy benzothiazole. Switching to phenyl-thiazole (as in LMK-5-67) preserves > 98% inhibition while removing the structural alert — a near-free win for any de-risking exercise.
The dataset also leaves two open questions the patent does not answer. First, only one cell line (LS174T) is tested — selectivity over non-c-MYC-driven CRC lines is asserted but not shown in the SAR table. Second, the dose-response data is partial: only ISQ-2, ISQ-7, ISQ-8, ISQ-9, ISQ-10, LMK-6-89, LMK-6-99 and a handful of others have full 4-point curves. Filling these gaps is a natural next step for any team building on this chemistry.
The most actionable insight from this patent is not which compound is best — it is that the patent's commercial claim is the combination, and the SAR data backs that up.
Frequently asked questions about US20240300921A1.
What is the lead compound in patent US20240300921A1?
The patent does not nominate a single lead, but the ISQ-1 compound code (1-methylindole-substituted 2-aminoquinoline with N(Me)2 at quinoline-7) is the most thoroughly profiled and is used as the partner in the BI2536 synergy study. LMK-5-67 (phenyl-thiazole + N(Me)2) is the most potent single agent at 99.8% inhibition @ 3 µM.
What cell line is the SAR run against?
All 95 records were generated against the LS174T human colon adenocarcinoma cell line — a c-MYC-driven CRC model frequently used to evaluate compounds targeting the c-MYC pathway. The endpoint is cell-proliferation inhibition over a 5-day exposure, dosed via culture-medium addition.
Why does the patent emphasize a Plk1 combination?
Polo-like kinase 1 (Plk1) is a downstream effector linked to c-MYC-driven proliferation. The patent reports that co-dosing the lead compound ISQ-1 with the clinical Plk1 inhibitor BI2536 produces a Bliss synergy score of 10.56 against LS174T — well above the +5 threshold conventionally used to distinguish synergy from additivity.
Are any of the disclosed compounds flagged for safety liabilities?
Yes. Two compounds — LMK-5-62 and LMK-5-68 — return a high mutagenicity flag in the in-silico Ames model. Both share a p-methoxy benzothiazole R1 group, a known structural alert. The remaining 38 compounds return no flags.
Where does the SAR data on this page come from?
The 95 activity records are extracted from Table 3 (page 31) of patent US20240300921A1 by the Eureka LS extraction engine. Multi-dimensional descriptors and the 211 activity-cliff pairs are computed automatically using standard cheminformatics methods.
Can I extract SAR data from any patent like this?
Yes — Eureka LS supports patents from USPTO, EPO, WIPO and CNIPA, either by patent number or PDF upload. The extraction engine generates a structured SAR table, the multi-dimensional descriptor profile, and activity-cliff comparisons in under 30 seconds. Try it on your patent of interest →
Where the data comes from.
- Patent US20240300921A1 — "Indole-substituted quinolines and their combination with Plk1 inhibitors for the treatment of cancer." Filed at the USPTO; activity data sourced from Table 3, page 31. https://patents.uspto.gov/patent/US20240300921A1
- Eureka LS SAR extraction engine — Auto-extracted compound table, dosing regimen, SMILES, and synergy data from the patent PDF. https://eureka.patsnap.com/ls/#/home/sar
- Eureka LS Multi-dimensional Overview — CLogP, TPSA, druglikeness, ligand efficiency, mutagenicity, scaffold and ring decomposition computed via standard cheminformatics methods.
- Eureka LS Activity Cliff Comparison — 211 pairwise comparisons of structural similarity (Tanimoto on Morgan fingerprints) and activity delta across the 40-compound library.
- BI2536 — Reference Plk1 inhibitor used in the patent's combination study. Steegmaier et al., Curr Biol 2007, 17(4): 316–322.
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