Cogent Biosciences, best known for challenging Blueprint’s position in KIT D816V kinase inhibition with bezuclastinib, now has two more assets for the sellside to try and value. Both are being revealed in preclinical posters at this weekend’s Triple (EORTC-NCI-AACR) symposium, and one – CGT6297 – could generate immediate interest. This small molecule is said to be specific for the H1047R mutation in PI3Kα, apparently with 25-fold selectivity over the wild-type form of this kinase. PI3Kα inhibition has come into focus as a means of avoiding the toxicity of hitting other PI3K isoforms, and recently two PI3Kα-selective inhibitors have impressed: Relay’s RLY-2608 and Scorpion’s STX-478. Still, both hit various PI3Kα mutations, and targeting a specific one offers even more precision; notably Lilly was working on the PI3Kα H1047R inhibitor LOXO-783, but discontinued it in favour of earlier-stage work. Interestingly, at last year’s San Antonio Breast Cancer Symposium Cogent mentioned CGT4824 as one PI3Kα H1047R-selective inhibitor it was working on, but this seems to have been eclipsed by CGT6297. Cogent’s other new pipeline entrant is the pan-KRAS(on) inhibitor CGT6737, a preclinical asset that will hope to compete against Revolution’s RMC-6236, Pfizer’s PF-07934040, Lilly’s LY-4066434 and BeiGene’s BGB-53038. Growing specificity: selected projects acting on PI3KαProjectCompanyTypeStatusPiqrayNovartisPI3Kα selective (mutant & wild-type)ApprovedItovebiRochePI3Kα selective (mutant & wild-type)*ApprovedRLY-2608RelayPI3Kα mutant-selective (wild-type sparing)Ph1STX-478ScorpionPI3Kα mutant-selective (wild-type sparing)Ph1OKI-219OnKurePI3Kα mutant-specific (H1047R)Ph1SNV4818SynnovationPI3Kα mutant-selective (wild-type sparing**)PreclinicalHP567HinovaPI3Kα mutant-specific (H1047R)PreclinicalCGT6297CogentPI3Kα mutant-specific (H1047R)PreclinicalLOXO-783LillyPI3Kα mutant-specific (H1047R)Discontinued in ph1RLY-5836RelayPI3Kα mutant-selective (wild-type sparing)Discontinued in ph1CGT4824CogentPI3Kα mutant-specific (H1047R)Discontinued in preclinicalNotes: *recently claimed also to degrade mutated PI3Kα; **earlier thought to have been H1047R mutation specific. Source: OncologyPipeline.
Cogent Biosciences, best known for challenging Blueprint’s position in KIT D816V kinase inhibition with bezuclastinib, now has two more assets for the sellside to try and value. Both are being revealed in preclinical posters at this weekend’s Triple (EORTC-NCI-AACR) symposium, and one – CGT6297 – could generate immediate interest. This small molecule is said to be specific for the H1047R mutation in PI3Kα, apparently with 25-fold selectivity over the wild-type form of this kinase. PI3Kα inhibition has come into focus as a means of avoiding the toxicity of hitting other PI3K isoforms, and recently two PI3Kα-selective inhibitors have impressed: Relay’s RLY-2608 and Scorpion’s STX-478. Still, both hit various PI3Kα mutations, and targeting a specific one offers even more precision; notably Lilly was working on the PI3Kα H1047R inhibitor LOXO-783, but discontinued it in favour of earlier-stage work. Interestingly, at last year’s San Antonio Breast Cancer Symposium Cogent mentioned CGT4824 as one PI3Kα H1047R-selective inhibitor it was working on, but this seems to have been eclipsed by CGT6297. Cogent’s other new pipeline entrant is the pan-KRAS(on) inhibitor CGT6737, a preclinical asset that will hope to compete against Revolution’s RMC-6236, Pfizer’s PF-07934040, Lilly’s LY-4066434 and BeiGene’s BGB-53038.
Growing specificity: selected projects acting on PI3Kα
| Project | Company | Type | Status |
|---|
| Piqray | Novartis | PI3Kα selective (mutant & wild-type) | Approved |
| Itovebi | Roche | PI3Kα selective (mutant & wild-type)* | Approved |
| RLY-2608 | Relay | PI3Kα mutant-selective (wild-type sparing) | Ph1 |
| STX-478 | Scorpion | PI3Kα mutant-selective (wild-type sparing) | Ph1 |
| OKI-219 | OnKure | PI3Kα mutant-specific (H1047R) | Ph1 |
| SNV4818 | Synnovation | PI3Kα mutant-selective (wild-type sparing**) | Preclinical |
| HP567 | Hinova | PI3Kα mutant-specific (H1047R) | Preclinical |
| CGT6297 | Cogent | PI3Kα mutant-specific (H1047R) | Preclinical |
| LOXO-783 | Lilly | PI3Kα mutant-specific (H1047R) | Discontinued in ph1 |
| RLY-5836 | Relay | PI3Kα mutant-selective (wild-type sparing) | Discontinued in ph1 |
| CGT4824 | Cogent | PI3Kα mutant-specific (H1047R) | Discontinued in preclinical |
