Dual kinase inhibitor targets heterogeneity in AML

SAN DIEGO—A dual kinase inhibitor shows potential for treating the heterogeneous acute myeloid leukemia (AML) population, researchers say.

The inhibitor, SEL24-B489, targets both PIM and FLT3 mutants. In experiments, it exhibited more consistent activity across AML cell lines than inhibitors directed only at PIM or FLT3.

SEL24-B489 also demonstrated synergistic activity with cytarabine, both in AML cell lines and mouse models of the disease.

The researchers believe these results suggest SEL24-B489 could potentially treat a range of AML patients and might prove effective regardless of FLT3 status.

“When you have a very heterogeneous population of AML patients, some of them have different FLT mutations, and the problem with FLT inhibitors has been the resistance that occurs in the tyrosine kinase domain,” said Krzysztof D. Brzózka, PhD, of Selvita, the Kraków, Poland-based company developing SEL24-B489.

“We believe that since FLT is upstream, and PIM kinases are downstream of the FLT signaling, we will have higher chances

of overcoming resistance because we are targeting the same pathway at 2 independent nodes.”

Dr Brzózka and his colleagues presented research to support this theory at the AACR Annual Meeting 2014 as abstract 1749.*

The researchers evaluated SEL24-B489 in a range of AML cell lines: MV4-11, MOLM-13, MOLM-16, KG-1, CMK, and HL-60. The drug showed “strong cytotoxicity” across the cell lines, independent of FLT3 status.

The team also compared SEL24-B489 to the PIM inhibitor AZD1208 and the FLT3 inhibitor AC220 in MV4-11 cell lines and MOLM-16 cell lines.

In MV4-11 cells, the IC₅₀ was 0.003 μM for AC220, 0.15 μM for SEL24-B489, and 2.24 μM for AZD1208. In MOLM-16 cells, the IC₅₀ was 0.07 μM for AZD1208, 0.1 μM for SEL24-B489, and >10 μM for AC220.

The researchers then evaluated SEL24-B489 in combination with cytarabine.

“The molecule shows very strong synergistic effects with cytarabine, both in vitro and in vivo,” Dr Brzózka said. “The combination index in vitro is approximately 0.1, 0.2. And in vivo, that translates to [nearly] 100% tumor growth inhibition.”

Tumor growth inhibition (TGI) measured 60% when mice received cytarabine alone at 50 mg/kg. TGI was 77% with SEL24-B489 alone at 25 mg/kg and 82% with SEL24-B489 alone at 50 mg/kg.

But with 25 mg/kg of SEL24-B489 and 50 mg/kg of cytarabine, TGI was 89%. And when both drugs were given at 50 mg/kg, TGI was 99%.

The researchers also assessed SEL24-B489 alone in mouse models of AML. In mice injected with MV4-11 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 50%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 80%.

In mice injected with MOLM-16 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 80%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 100%.

Finally, the team evaluated the safety of SEL24-B489 via repeated 5-day and 10-day toxicology studies in rats.

And they concluded that doses of 100 mg/kg QD x 5 and 25 mg/kg BID x 10 were safe, based on data concerning body weight gain, as well as results of clinical chemistry, hematology, necropsy, and histological analyses.

“Overall, SEL24-B489 has very good oral bioavailability and initial safety profiling,” Dr Brzózka said. “Both in vitro and in vivo, it shows a pretty promising therapeutic index.”

He and his colleagues are now studying SEL24-B489 in dogs, and Selvita is looking for a partner company to help move the drug to phase 1 trials.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—A dual kinase inhibitor shows potential for treating the heterogeneous acute myeloid leukemia (AML) population, researchers say.

The inhibitor, SEL24-B489, targets both PIM and FLT3 mutants. In experiments, it exhibited more consistent activity across AML cell lines than inhibitors directed only at PIM or FLT3.

SEL24-B489 also demonstrated synergistic activity with cytarabine, both in AML cell lines and mouse models of the disease.

The researchers believe these results suggest SEL24-B489 could potentially treat a range of AML patients and might prove effective regardless of FLT3 status.

“When you have a very heterogeneous population of AML patients, some of them have different FLT mutations, and the problem with FLT inhibitors has been the resistance that occurs in the tyrosine kinase domain,” said Krzysztof D. Brzózka, PhD, of Selvita, the Kraków, Poland-based company developing SEL24-B489.

“We believe that since FLT is upstream, and PIM kinases are downstream of the FLT signaling, we will have higher chances

of overcoming resistance because we are targeting the same pathway at 2 independent nodes.”

Dr Brzózka and his colleagues presented research to support this theory at the AACR Annual Meeting 2014 as abstract 1749.*

The researchers evaluated SEL24-B489 in a range of AML cell lines: MV4-11, MOLM-13, MOLM-16, KG-1, CMK, and HL-60. The drug showed “strong cytotoxicity” across the cell lines, independent of FLT3 status.

The team also compared SEL24-B489 to the PIM inhibitor AZD1208 and the FLT3 inhibitor AC220 in MV4-11 cell lines and MOLM-16 cell lines.

In MV4-11 cells, the IC₅₀ was 0.003 μM for AC220, 0.15 μM for SEL24-B489, and 2.24 μM for AZD1208. In MOLM-16 cells, the IC₅₀ was 0.07 μM for AZD1208, 0.1 μM for SEL24-B489, and >10 μM for AC220.

The researchers then evaluated SEL24-B489 in combination with cytarabine.

“The molecule shows very strong synergistic effects with cytarabine, both in vitro and in vivo,” Dr Brzózka said. “The combination index in vitro is approximately 0.1, 0.2. And in vivo, that translates to [nearly] 100% tumor growth inhibition.”

Tumor growth inhibition (TGI) measured 60% when mice received cytarabine alone at 50 mg/kg. TGI was 77% with SEL24-B489 alone at 25 mg/kg and 82% with SEL24-B489 alone at 50 mg/kg.

But with 25 mg/kg of SEL24-B489 and 50 mg/kg of cytarabine, TGI was 89%. And when both drugs were given at 50 mg/kg, TGI was 99%.

The researchers also assessed SEL24-B489 alone in mouse models of AML. In mice injected with MV4-11 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 50%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 80%.

In mice injected with MOLM-16 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 80%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 100%.

Finally, the team evaluated the safety of SEL24-B489 via repeated 5-day and 10-day toxicology studies in rats.

And they concluded that doses of 100 mg/kg QD x 5 and 25 mg/kg BID x 10 were safe, based on data concerning body weight gain, as well as results of clinical chemistry, hematology, necropsy, and histological analyses.

“Overall, SEL24-B489 has very good oral bioavailability and initial safety profiling,” Dr Brzózka said. “Both in vitro and in vivo, it shows a pretty promising therapeutic index.”

He and his colleagues are now studying SEL24-B489 in dogs, and Selvita is looking for a partner company to help move the drug to phase 1 trials.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—A dual kinase inhibitor shows potential for treating the heterogeneous acute myeloid leukemia (AML) population, researchers say.

The inhibitor, SEL24-B489, targets both PIM and FLT3 mutants. In experiments, it exhibited more consistent activity across AML cell lines than inhibitors directed only at PIM or FLT3.

SEL24-B489 also demonstrated synergistic activity with cytarabine, both in AML cell lines and mouse models of the disease.

The researchers believe these results suggest SEL24-B489 could potentially treat a range of AML patients and might prove effective regardless of FLT3 status.

“When you have a very heterogeneous population of AML patients, some of them have different FLT mutations, and the problem with FLT inhibitors has been the resistance that occurs in the tyrosine kinase domain,” said Krzysztof D. Brzózka, PhD, of Selvita, the Kraków, Poland-based company developing SEL24-B489.

“We believe that since FLT is upstream, and PIM kinases are downstream of the FLT signaling, we will have higher chances

of overcoming resistance because we are targeting the same pathway at 2 independent nodes.”

Dr Brzózka and his colleagues presented research to support this theory at the AACR Annual Meeting 2014 as abstract 1749.*

The researchers evaluated SEL24-B489 in a range of AML cell lines: MV4-11, MOLM-13, MOLM-16, KG-1, CMK, and HL-60. The drug showed “strong cytotoxicity” across the cell lines, independent of FLT3 status.

The team also compared SEL24-B489 to the PIM inhibitor AZD1208 and the FLT3 inhibitor AC220 in MV4-11 cell lines and MOLM-16 cell lines.

In MV4-11 cells, the IC₅₀ was 0.003 μM for AC220, 0.15 μM for SEL24-B489, and 2.24 μM for AZD1208. In MOLM-16 cells, the IC₅₀ was 0.07 μM for AZD1208, 0.1 μM for SEL24-B489, and >10 μM for AC220.

The researchers then evaluated SEL24-B489 in combination with cytarabine.

“The molecule shows very strong synergistic effects with cytarabine, both in vitro and in vivo,” Dr Brzózka said. “The combination index in vitro is approximately 0.1, 0.2. And in vivo, that translates to [nearly] 100% tumor growth inhibition.”

Tumor growth inhibition (TGI) measured 60% when mice received cytarabine alone at 50 mg/kg. TGI was 77% with SEL24-B489 alone at 25 mg/kg and 82% with SEL24-B489 alone at 50 mg/kg.

But with 25 mg/kg of SEL24-B489 and 50 mg/kg of cytarabine, TGI was 89%. And when both drugs were given at 50 mg/kg, TGI was 99%.

The researchers also assessed SEL24-B489 alone in mouse models of AML. In mice injected with MV4-11 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 50%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 80%.

In mice injected with MOLM-16 cells, SEL24-B489 at 25 mg/kg BID reduced tumor volume by more than 80%, when compared to untreated control mice. And SEL24-B489 at 75 mg/kg BID reduced tumor volume by more than 100%.

Finally, the team evaluated the safety of SEL24-B489 via repeated 5-day and 10-day toxicology studies in rats.

And they concluded that doses of 100 mg/kg QD x 5 and 25 mg/kg BID x 10 were safe, based on data concerning body weight gain, as well as results of clinical chemistry, hematology, necropsy, and histological analyses.

“Overall, SEL24-B489 has very good oral bioavailability and initial safety profiling,” Dr Brzózka said. “Both in vitro and in vivo, it shows a pretty promising therapeutic index.”

He and his colleagues are now studying SEL24-B489 in dogs, and Selvita is looking for a partner company to help move the drug to phase 1 trials.

*Information in the abstract differs from that presented at the meeting.