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DRUG CLASS:

PI3Kα H1047R mutation inhibitor

4ms
Free energy landscape of the PI3Kα C-terminal activation. (PubMed, Comput Struct Biotechnol J)
Moreover, we show that in the H1047R mutant, the cavity, where the allosteric ligands STX-478 and RLY-2608 bind, is more accessible contrary to the WT. This study provides insights into the molecular mechanisms underlying activation of oncogenic PI3Kα by C-terminal mutations and represents a valuable resource for continued efforts in the development of mutant selective inhibitors as therapeutics.
Journal
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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PIK3CA mutation • PIK3CA H1047R • PIK3CA G1049R
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RLY-2608 • STX-478
4ms
PIKASSO-01: A Study of LOXO-783 in Patients With Breast Cancer/Other Solid Tumors (clinicaltrials.gov)
P1, N=193, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting | N=400 --> 193
Enrollment closed • Enrollment change • Combination therapy • Metastases
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA H1047R
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paclitaxel • Verzenio (abemaciclib) • fulvestrant • letrozole • anastrozole • exemestane • imlunestrant (LY3484356) • LOXO-783
5ms
A Study of [14C]-LOXO-783 in Healthy Adult Participants (clinicaltrials.gov)
P1, N=16, Completed, Eli Lilly and Company | Not yet recruiting --> Completed
Trial completion
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LOXO-783
5ms
A Study to Evaluate the Effect of Food on LOXO-783 in Healthy Participants (clinicaltrials.gov)
P1, N=42, Completed, Eli Lilly and Company | Recruiting --> Completed
Trial completion
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LOXO-783
8ms
STX-478-101: First-in-Human Study of STX-478 as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov)
P1/2, N=400, Recruiting, Scorpion Therapeutics, Inc. | Trial completion date: Apr 2028 --> Feb 2029 | Trial primary completion date: Apr 2026 --> Feb 2027
Trial completion date • Trial primary completion date • Combination therapy • Metastases
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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PIK3CA mutation
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fulvestrant • STX-478
9ms
STX-478-101: First-in-Human Study of STX-478 as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov)
P1/2, N=400, Recruiting, Scorpion Therapeutics, Inc. | N=220 --> 400 | Trial completion date: Jun 2026 --> Apr 2028
Enrollment change • Trial completion date • Combination therapy • Metastases
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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PIK3CA mutation
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fulvestrant • STX-478
9ms
Enrollment open • Combination therapy • Metastases
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Herceptin (trastuzumab) • fulvestrant • OKI-219
11ms
New P1 trial
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Herceptin (trastuzumab) • fulvestrant • OKI-219
1year
A New Wave of PI3Kα Inhibitors. (PubMed, Cancer Discov)
However, in contrast to the FDA-approved PI3Kα isoform-selective inhibitor alpelisib, STX-478 does not induce hyperglycemia or other metabolic dysfunctions. See related article by Buckbinder et al., p. 2432 (7).
Journal
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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PIK3CA mutation
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Piqray (alpelisib) • STX-478
1year
OKI-219, a PI3KαH1047R-mutant-selective inhibitor demonstrates efficacy as a single agent and drives combination responses with standard of care therapies in pre-clinical PI3KαH1047R mutant breast cancer models. (SABCS 2023)
Although targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies, treatment with non-mutant selective PI3Kα inhibitors such as alpelisib is associated with significant toxicities such as hyperglycemia, due to on-target inhibition of the wild-type enzyme...Moreover, OKI-219 dosed in combination with the selective estrogen receptor degraders (SERDs) fulvestrant, elacestrant or camizestrant showed significant combination benefit leading to tumor regressions of up to 100% in the ER+ H1047R mutant breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. Dosing OKI-219 in combination with HER2-inhibitors, such as tucatinib, led to tumor regressions in the ER-HER2+ and H1047R mutant breast cancer CDX model HCC1954, also at doses where no regressions were observed with single agent treatment. These data indicate that OKI-219 offers improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. OKI-219 is advancing into clinical trials.
Preclinical
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ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA H1047R • ER positive + PIK3CA H1047R • ER negative + HER-2 positive + PIK3CA H1047R
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Piqray (alpelisib) • fulvestrant • Tukysa (tucatinib) • Orserdu (elacestrant) • camizestrant (AZD9833) • OKI-219
1year
STX-478 is a potentially best-in-class mutant-selective PI3Kα inhibitor that demonstrates robust efficacy in ER+ breast cancer models as monotherapy and in combination with standard of care agents (SABCS 2023)
In a panel of PI3Kα mutant CDX and PDX models, STX-478 provided efficacy that was similar or superior to higher than clinically achievable doses of alpelisib...In a representative PDX model, STX-478 combined with the ER degrader fulvestrant and palbociclib was well tolerated for > 90 days of dosing in mice and resulted in durable tumor regressions that were superior to STX-478 alone...These properties combined with the potential for CNS penetration and excellent pharmacokinetic profile in higher species make STX-478 a potentially best-in-class mutant-selective PI3Kα inhibitor. STX-478 is currently being evaluated in a Phase I clinical trial (NCT05768139).
Clinical • Preclinical • Combination therapy
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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PIK3CA mutation
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Ibrance (palbociclib) • Piqray (alpelisib) • fulvestrant • STX-478
1year
STX-478, a Mutant-Selective, Allosteric PI3Ka Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Ka-Mutant Xenografts. (PubMed, Cancer Discov)
The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme...Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models...STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models.
Journal
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation
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Piqray (alpelisib) • fulvestrant • STX-478
1year
A Study of [14C]-LOXO-783 in Healthy Adult Participants (clinicaltrials.gov)
P1, N=16, Not yet recruiting, Eli Lilly and Company
New P1 trial
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LOXO-783
over1year
Enrollment change • Combination therapy • Metastases
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA H1047R
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paclitaxel • Verzenio (abemaciclib) • fulvestrant • letrozole • anastrozole • exemestane • imlunestrant (LY3484356) • LOXO-783
2years
P1 data
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA H1047R
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LOXO-783
2years
LOXO-783: A potent, highly mutant selective and brain-penetrant allosteric PI3Kα H1047R inhibitor in combination with standard of care (SOC) treatments in preclinical PI3Kα H1047R-mutant breast cancer models (SABCS 2022)
Results Combining LOXO-783 with either fulvestrant (FUL; CI at 50% inhibition = 0.28) or imlunestrant (CI at 50% inhibition = 0.43) showed increased efficacy in cell proliferation assays using the HR+, HER2-, PI3Kα H1047R- mutant T47D model...Similar results were observed in a T47D model engineered to express ESR1 D538G, as well as in an HR+, HER2- PI3Kα double in-cis mutant model (H1047R/D350G) also harboring ESR1 D538G and derived from a patient who had progressed on prior letrozole plus taselisib...Extending these studies to additional treatment settings, LOXO-783 was similarly efficacious as a single agent in abemaciclib-resistant and abemaciclib/FUL double-resistant models, and was additive in combination with paclitaxel in a triple negative breast cancer model in vitro and in vivo...LOXO-783 is also efficacious in ESR1 mutant as well as in abemaciclib and abemaciclib/FUL double-resistant models. A phase 1 trial of LOXO-783 alone or in combination with anticancer therapies is ongoing (PIKASSO-01; NCT05307705).
Preclinical • Combination therapy
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA H1047R • ER D538G • ESR1 mutation • PIK3CA D350G
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paclitaxel • Verzenio (abemaciclib) • fulvestrant • letrozole • taselisib (GDC-0032) • imlunestrant (LY3484356) • LOXO-783
2years
STX-478, a mutant-selective PI3Kα H1047X inhibitor clinical candidate with a best-in-class profile: Pharmacology and therapeutic activity as monotherapy and in combination in breast cancer xenograft models (SABCS 2022)
When combined with fulvestrant, lapatinib, or abemaciclib, STX-478 demonstrated synergistic anti-proliferative activity in cell lines with relevant ER/HER2 status...In the T47D (PI3Kα H1047R) breast cancer model, STX-478 (100 mg/kg) monotherapy caused tumor regression whereas alpelisib caused only stasis...In an ER+/HER2+ PDX model (PI3Kα H1047R/R108H), palbociclib and STX-478 (100 mg/kg) monotherapy resulted in similar efficacy while the combination was well tolerated and yielded tumor regression...The significant CNS exposure of STX-478 is expected to enable this treatment for patients with brain tumors and brain metastases not afforded by existing options. STX-478 is currently in IND enabling studies and is expected to enter human clinical trials in 2023.
Preclinical
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA H1047R • PIK3CA H1047
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Ibrance (palbociclib) • lapatinib • Piqray (alpelisib) • Verzenio (abemaciclib) • fulvestrant • STX-478
almost3years
Discovery and characterization of a mutant selective PI3KαH1047Xinhibitor with a best-in-class profile (AACR 2022)
Alpelisib is a PI3Kα isoform-selective, orthosteric kinase inhibitor, having equivalent activity on wild-type (wt) and mutant (mt) forms and was approved to treat PI3Kα mt, HR+/HER2- breast cancer in combination with fulvestrant, nearly doubling progression-free survival (Andre 2019)...ST-814 has robust anti-tumor activity in PI3KαH1047X in xenografts, with efficacy similar or superior to alpelisib dosed at 50 mg/kg (Table 1)...A clinical candidate from this program is currently in IND enabling studies. >
Late-breaking abstract
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HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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HER-2 negative • PIK3CA mutation • PIK3CA H1047R • PIK3CA E545 • PIK3CA H1047 • PIK3CA E542 • PIK3CA H1047X
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Piqray (alpelisib) • fulvestrant • STX-478